Thursday, January 24, 2008

Levine - Assessing The Playing Field

The Wyeth v. Levine case is such a big deal that you can bet we’ll be discussing it a lot. For one thing, it has the potential to obliterate entire mass tort litigations at a stroke. Since we’re mass tort kind of guys, we’re keeping a mental hit list of where we’d strike first after a favorable outcome – but that’s not something we’d give away here - not now, anyway.

On the other hand, it’s not the millennium either. Levine won’t end modern prescription drug product liability litigation as we know it. But a favorable preemption ruling in Levine could well bring about a good, and long overdue, pruning. We see it – at a minimum – as eliminating a host of claims involving situations where the FDA has authoritatively spoken on a particular risk involving a particular drug. Several MDLs could well go bye-bye as a result.

Then again, we could lose. The Court could go the other way and restore the pre-Buckman world where guys like us, defending pharmaceutical companies, would gaze wistfully at the medical device folks (which also includes guys like us) and wish that we had a preemption defense, too.

Big issues raised in the Levine briefing to date, which means in the briefing on the certiorari (typically abbreviated “cert.” – referring to an obsolescent name for discretionary appellate review) petition – include:

  • Are FDA-approved labels a “minimum standard” or something more than that? We’ve already had plenty to say on this, here specifically in connection with Levine, and here more generally.
  • Is the defendant free to use a CBE (“changes being effected”) supplement to make a unilateral change that strengthens or adds a warning without prior FDA approval where the FDA already addressed that particular labeling issue? We’ve already had plenty to say on this issue, here.
  • Does the presumption against preemption apply in a conflict preemption case? We’ve already had plenty to say on this issue, here.
  • Does “direct and positive conflict” language in an uncodified part of the 1962 amendments to the FDCA oust implied “obstacle” preemption? We’ve touched on this issue here, here, and here, but haven’t devoted a lot of time to it yet. We will, but not today.
  • What degree of deference should be given to the FDA’s recent statements about preemption? We’ve already had plenty to say on this issue here.
And if you don’t want to take our word for it, all of the briefs on the cert. petition in Levine are available through the auspices of the really excellent SCOTUSblog – which is probably the legal blog we use more than any other in our actual, paying work. You can find links to all the Levine briefs right here (Levine is the second case on the list).

One other thing before we get to the point of this post. Contrary to the impression we had when the Supreme Court granted cert. last week, it’s not yet 100% sure that the Court will hear the Levine case this term. There were 6 cert. grants on the 1/18/08 order, and there are only two open slots for oral argument. For details, see the ever-informative SCOTUSblog. We think it’s likely that Levine will be one of those two because: (1) it is one of the two longest-pending cases on the Supreme Court’s docket (there’s no mystery to figuring that out; just look at the order for the lowest docket numbers after the “06-“); and (2) the Court already has two other FDCA-related preemption cases on its docket (if you don’t already know that, why are you reading this blog?), and they’ll probably want to decide them as a package. If the Court had wanted to wait, it would have followed the SG’s recommendation and simply held the Levine petition.

Getting Levine heard this term is – like everything else about the case – a big deal. Why? Politics. The legal positions taken by the SG and the FDA reflect the broader views of the administration that’s in office. We’d have to say that preemption in prescription drug and medical device tort litigation has fared pretty well with the current crew. But we read the same polls everybody else does, and we know that, for any case that gets held over for the next Supreme Court term, there’s a pretty good chance that a new administration’s political appointees will have a different take on the preemption issue.

So we’ll see what happens.

Now to the point – and yes, we do have one. There’s an old saying that “hard cases make bad law.” We don’t know who said it (somebody named “Maxim”?), but we think it’s true. So a logical first place to start when approaching something as controversial as the Levine case is with the facts. Specifically, how good are the facts for implied conflict preemption?

Well, first of all, Levine doesn’t involve any of the real preemption battleground drugs – it’s not an SSRI suicide case, nor does it involve Elidel, Prempro, Vioxx, Nexium, or any other drug that has produced multiple preemption decisions. See our Prescription Drug Preemption Scorecard for a complete list. That means Levine presents a playing field that’s relatively unimpeded by prior precedent.

That’s not to say that the facts are particularly recent – they’re anything but that. The drug in Levine is Phenergan, something that’s been on the market since 1955, and which has several uses. You may even have taken it as the active ingredient in some cough syrups. We have. It tastes rather revolting (at least it used to), but it will knock out a cough.

But that’s not the only use for Phenergan. It’s also used to treat really, really bad nausea of the sort that can land somebody in the hospital with dehydration. In these severe cases, it’s not enough just to take the stuff orally like we did with cough syrup. For faster relief, Phenergan can be given intravenously.

Beyond that, there are a couple of ways to administer a drug intravenously. There’s the “drip” method, where the fluid goes into your body at whatever rate your body wants to absorb it, and there’s the “push” method, which is used in the more serious cases when it’s necessary to get more of the stuff into you faster. No rocket science there.

Levine involves a medical decision to administer Phenergan by IV push, so this particular prescriber must have thought that the plaintiff-patient absolutely, positively needed the stuff.

Why do we say that? Well, like any prescription drug, Phenergan has inherent risks. In Levine, that risk was quite severe indeed. We don’t know why, and for purposes of Levine we don’t have to know, but if Phenergan gets into an artery – as opposed to a vein – it can cause gangrene.

That’s some risk – and that’s apparently what happened to the plaintiff in Levine. Somehow (and the briefs aren’t saying), the IV needle for the plaintiff’s Phenergan ended up poked into her artery rather than into the intended vein. As a result (we’re assuming medical causation for purposes of this discussion; we don’t know how much it’s disputed), the plaintiff lost her forearm to gangrene. That’s big damages, if there’s liability.

Gangrene is not only a serious risk of Phenergan but – more importantly for preemption purposes – it is also a known one. There was an FDA-approved warning about gangrene on the Phenergan that the plaintiff took. Naturally, the plaintiff claims that this label wasn’t enough, since that’s what plaintiffs have to do. If the drug’s label is adequate, the plaintiff loses. Plaintiffs don’t like to lose any more than we do.

First good fact for the defendant: The warning in this case was anything but wishy-washy. It mentioned the risks of “arterial” exposure in several places – including in boldface, all caps type: “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.” It expressly told the treating doctor (under the learned intermediary rule all prescription drug warnings are addressed to MDs, not to patients) to consider whether an IV push method of injection was appropriate at all, given the risk. The warning advised “extreme care” not to get any Phenergan into the patient’s arteries. It stated that if anything went wrong and that did happen, it was “likely” that serious injury, specifically, “gangrene requiring amputation,” would result:


Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation [that’s “missing the vein and putting the drug in the surrounding tissue” for you non-doctors] or inadvertent intra-arterial [that’s “into the artery”] injection. Reports compatible with [that means “that could involve”] inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal [that means “relatively far away”] vessels, and resultant gangrene requiring amputation are likely under such circumstances.

The label in question mentioned “gangrene” no less than four times.

In short, the defendant gave a warning that: (1) expressly mentioned the particular risk (gangrene), (2) described how serious it was (“likely” if the drug is introduced into the artery), (3) told doctors how to avoid the risk (use IV-drip in preference and be very careful), and (4) used a satisfactory format (all caps and bold). There are a lot of places – but apparently not the Peoples’ Republic of Vermont – where the Levine case would have ended with a summary judgment ruling that this warning was adequate as a matter of state law. You can find a complete list of those cases on pages 2.04-31 to -35 (there are a lot of them) in Bexis’ book.

We’ll tell you right up front that all this description comes from the defendant’s opening papers that sought (now, successfully) to get the Supreme Court to take the case. Come on, we’re defense lawyers. Do you think we’d take the facts from the plaintiff’s point of view? If you want a plaintiff-side slant, maybe you’ll find it here or here. Or maybe not. You’re not likely to hear about facts from a lawyer (us included), unless they help his/her side.

Anyway, we’d have to say that the Phenergan warning is pretty darn good – adequate as a matter of law in a lot of jurisdictions. So how does the plaintiff claim it’s inadequate if it specifically mentions the risk and tells the prescriber how to avoid it?

Good question.

The answer to that question is where preemption comes in. The plaintiff doesn’t really find fault with what the label says about the risks of IV-push administration of Phenergan. What she claims is that the defendant must go further and say don’t use IV-push at all – that the risks are so awful (and gangrene is surely that) that the added benefit of getting more of the drug into the body faster just isn’t worth it – ever. In medical/legal/regulatory jargon, that kind of a “don’t do it at all” warning is called a “contraindication.”

As you can tell, a contraindication is a very serious kind of warning. For that reason, the FDA has strict standards that have to be met before a contraindication can be approved. They’re found in 21 C.F.R. §201.57(d). That regulation requires that a contraindication must relate to a “known hazard” (the risk in Levine seems to meet that) and due to that hazard “the risk of use clearly outweighs any possible benefit.” (There’s where a contraindication doesn’t cut the regulatory mustard, in the opinion of the FDA, if not the plaintiff.)

The reason for preemption is that, in the case of Phenergan, the FDA had looked at all this itself. Gangrene was a known risk, first seen in 1967. The risk was reported to the FDA, and the resultant warning about that risk went through several versions over the years. By 1981 it said that, due to various risks, the IV-drip method was “usually preferable.” During that 14 year period before 1987, the FDA never once sought a contraindication, despite the severe nature of the risk.

There was a general reformatting of prescription drug labeling in the late 1980s, and Phenergan was part of that. In particular, the FDA sought a number of label changes relating to “recognition and management of unintended intra-arterial injection.” One of these was to enhance what the label said about IV-drip. The FDA wanted the label changed to state that the drip (as opposed to the push) method “may enhance the possibility of detecting arterial placement” – that is, the doctor could tell more easily if there was a potentially dangerous screw up. The approved label change also pointed out that the drip method “results in delivery of a lower concentration of any arteriolar irritant” (it’s words like “arteriolar” – and “perivascular extravasation” – that show why we have a learned intermediary rule). Thus doctors (who know these big words) understood that, if there actually is a screw up, and only drip is used, less Phenergan (the “arteriolar irratant”) gets where it doesn’t belong.

Again, that’s as far as the FDA ever went. It never suggested that IV-push was so risky that it should be contraindicated.

Second good fact for the defendant. The defendant manufacturer then attempted to make more changes to the Phenergan label that the FDA rejected. It made submissions in 1988 and 1989. Their exact nature isn’t particularly important, since they were rejected, but they included both inadvertent intra-arterial injection and other stuff not involved in the Levine case. This time, however, the FDA said “no.” That “no” occurred in 1997, about three years before the incident that involved this plaintiff and nearly a decade after the revised labeling was submitted.

We expect somebody to ask why the FDA took so long – the entire term of Bush I and the first Clinton term. It’s a good question, but we have no idea what the answer is. Maybe Dr. David Kessler, who ran the FDA for most of that time, does.

All we know is that, when the FDA did act, it said “no.”

Anyway, by letter dated February 21, 1997, the FDA told the manufacturer to ditch the new (or by that point, not so new) labeling changes – at least the part about intra-arterial injection: “f. Inadvertent Intra-arterial Injection – Retain verbiage in current label.” (This is in the appendix to the defendant’s papers, 160-163a for those of you keeping score at home.)

Well, when the FDA says “no,” that’s what a manufacturer does - if it likes to keep being able to sell its product. Thus, the new labeling was withdrawn and the old label apparently resubmitted (we’re not FDA regulatory experts, and we’re not sure why it was necessary to do that (perhaps other changes went through), but that seems to be what happened). The result was a second letter from the FDA dated September 18, 1998, reiterating that the manufacturer was not to change the label: “The final printed labeling (FPL) for the package insert must be identical to the draft package insert submitted May 8, 1998.” (Again, see the defendant’s appendix at 164-166a.)

Looking at those facts, we’d have to say that Levine presents a preemption case that we’re quite comfortable with. The issue of gangrene and intravenous administration is plainly not anything “new” that would justify use of a “change being effected” supplement – either under the FDA’s understanding of the CBE exception at the time that process was created, or under the Agency’s currently proposed revision to the CBE regulation.

Not only that, but Levine is a case where you can argue that the FDA said “no,” but the plaintiff is trying to get the common law to say “yes.” We like that kind of case because it’s a simple, powerful argument. The plaintiffs will undoubtedly try to nitpick exactly what label changes were before the FDA, but “retain” and “identical” are rather difficult words to get around. It’s like we tell our kids – “what part of ‘no’ don’t you understand?”

And there’s more. The plaintiff’s proposition in Levine is that the common law should essentially prohibit a medical procedure – by declaring that IV-push should be contraindicated. This is not just a matter of telling doctors to do something differently, but of telling them not to do it at all. What the plaintiff makes is a risk/benefit claim, not the usual inadequate warning claim. This sort of claim is considerably more extreme than those seen in most prescription drug product liability cases, and it plays right into the FDA’s greatest strength – it’s always been the Agency’s job to make risk/benefit decisions of this sort. Accordingly we think (hope?) it will prove more difficult for the Supreme Court to endorse such a claim than might be the case if a run-of-the-mill inadequate warning (e.g., “you should have stated the risk more clearly”) claim were at issue.

Finally, in 2006 the FDA set out six categories of failure to warn claims that it thought were preempted by the FDCA. We think that at least two of them are potentially relevant:

  • claims that a manufacturer failed to warn not including contraindications or warnings that are not supported by evidence that meets the FDA’s scientific standards; and
  • claims that a manufacturer failed to warn by not including a statement in its labeling or in advertising that the FDA had prohibited the manufacturer from stating.
71 Fed. Reg. 3922, 3936 (FDA Jan. 24, 2006) (emphasis added).

Whether the first exception applies depends upon facts that we don’t have, but it certainly doesn’t appear from what the FDA concluded that the “risk clearly outweigh benefit” standard of §201.57(d) is met. The second category of FDA-recognized preemption clearly applies, since the FDA stated explicitly that the manufacturer was to continue using the label at issue without any changes.

Another thing we like about the Levine facts is what they apparently don’t contain. For that, we do look at the plaintiff’s papers.

Reading the plaintiff’s brief against certiorari, we find no claim that the defendant misstated or understated the risk in its label. That’s rare in a drug labeling case, and quite good for the defendant. While that’s not really surprising, given the plaintiff’s contraindication argument, it’s one less bunch of adverse facts to have to deal with. Going further, there’s no suggestion that the defendant ever hid anything from the FDA – and plaintiffs absolutely love to call defendants criminals any time they possibly can. While we don’t think misrepresentations to the FDA should matter under Buckman Co. v. Plaintiffs’ Legal Committee, 531 U.S. 341 (2001), as a matter of atmospherics they usually do.

We’ll go through the legal arguments in Levine soon enough – probably after the top-side merits briefs are filed – but looking at the case purely from a factual perspective, we have to say that we’re encouraged by what we see.

2 comments:

PhD said...

Although I am against FDA preemption in general, I agree that the Levine case is not a strong one.

My question is this: If one honestly wants to put the preemption issue to the test - as sensible or non-sensical policy - wouldn't it be better to have a case in which there was, indeed, more ambiguity in the CBE issue, a company's compliance (not only in letter but in spirit), whether there were questions of suppressed studies or delayed reporting (which FDA/ORA chose to tolerate, as they normally do), and so on?

I understand that, from the perspective of defense attorneys, these "messier" questions do, indeed, make preemption harder to argue. And, indeed, swallow. Discovery might well reveal facts that show how limited assurance and accountability FDA compliance can actually provide.

So the question is really philosophical and ethical (not being a lawyer, I can ask it).

Does it matter to defense attorneys whether they contribute to rulings that may have broad policy implications that are a plus for their clients but a negative for public health in general?

Or is it solely up to the Supreme Court to think through such wider implications in the way they frame a ruling in a particular case?

Hopelessly naive? Well, it is a genuine question. (I understand it will be argued that what is good for a client is good for public health in general. I would love to see a response premised at least on the _possibility_ that this was not the case.)

laura said...

http://jaynesdays.blogspot.com/

This is a link to a blog that clearly explains the flawed reasoning that medical device and drug preemption advocates are dealing with. Far from being an all knowing, faultless administration, the FDA is actually fraught with corruption,lack of funds, overwork, and the inability to fully investigate and follow up on products they have approved for market. Should the public be expected to bow to the FDA's decisions and be left with no recourse when, by the FDA's own admission, they are a flawed administration?