Thursday, January 17, 2008

Why Fixing The FDA's CBE ("Changes Being Effected") Regulation Is A Big Deal

The other day we got a tip that the FDA had just posted something on its website that we’d want to read. Even though we were both swamped (Herrmann was preparing for yet another trial, and Bexis had two appellate briefs to finish, including one about “the largest class certified in history” – the court’s words, not his), we took a look and, sure enough, the FDA had just posted modifications to its CBE (“changes being effected”) regulations. It was all we could do to throw up a short post about that (first on the web, though), promising more later.

This is later.

In the meantime, even our little post got picked up by the Wall Street Journal and Pharmalot. We got a bunch of requests for comment by the press. The FDA’s proposal hadn’t been public more than 24 hours before the plaintiffs’ lobby, the American Association for Tort Taxation … er ... Trial Lawyers … er ... Justice (?!?) demanded that the FDA withdraw it. Not only that, but the FDA’s proposal is the lead story in this morning’s Product Liability 360 alert (quoting Bexis). Oh yeah, it also made yesterday our heaviest traffic day ever.

So what’s the big deal?

The big deal was summed up in the title to our first little post. The FDA’s rules change, although looking at first glance like just so much administrative tweeking, will “Assist Preemption.” It's not so much that the FDA got it right about preemption – it’s done that before with its recent amicus briefs and with its Preemption Preamble to its January, 2006 Final Rule about labeling – but that the FDA it got it right in the right way.

OK, guys, stop beating around the bush, what do you mean by that?

Well, imagine you’re a federal agency. Congress has charged you with protecting the public health by regulating certain products. To ride herd over what the folks you’re supposed to regulate say about their products, you’ve got pre-approval power. So you tell them, “everything you say, you have to run by us first.”

That’s well and good, but what about emergencies? As a big federal agency, you need a little time to get your act in gear. You know that, and you don’t want people to get hurt while time’s a wasting. So when you’re writing your regs, you include an exception for emergency changes that add or strengthen warnings. You add other stuff as well (you don’t care when somebody moves and wants to put its new address on a label, either).

Because you’re a federal agency, you write up a great big submission in the Federal Register explaining what you meant by your reg and the exceptions you made to it.

The regulation sits around for a long time and everything’s working pretty well. Then a bunch of lawyers come into the picture. They want to take away your final say about what the folks you regulate can tell the public about your products. They want to take that final say for themselves because they can make a lot of money blaming those folks for not having told the public (always after the fact) what they want them to. They spot your regulation – intended for emergencies – and, “aha,” it doesn’t specifically state that it's limited to emergencies.

So this bunch of lawyers starts claiming that the regulated folks can make any changes they want to anything at all that those folks say, so long as it adds or strengthens a warning - even though you, the agency, just went over that same thing yesterday and told those folks what to do. They make this argument where there isn’t anything that’s new or different and demand that the regulated folks pay them a lot of money for doing what you, the agency, told them to do. They say that the folks you regulate shouldn’t have done what you told them to do, but should have done something else.

What do you, the agency, do then? Well, first you say “come on, that’s not what I meant. I told everyone what this reg was for right there in the Federal Register.” You say that, first, in amicus briefs. But these lawyers are pretty persuasive. They say your regulation isn’t that detailed, that courts don’t have to care what you say, and that they should ignore you.

Well, as a federal agency, you don’t like courts telling you to pound sand. So you go one step further. You go back to the Federal Register and say, formally, this is what we intended that regulation to mean, and it doesn’t mean that anybody can make any labeling changes they want about anything at any time.

But the lawyers still tell the courts to ignore you, and a lot of them do. The lawyers say you're all wet, that even if that’s what you meant the regulation to do, it’s not what the regulation actually says. It just says “add or strengthen warnings.”

What do you as a rational federal agency do then?

You decide to change the regulation itself to say precisely what you meant it to say all along, that’s what. You take what you previously said in the Federal Register and stick it right into the text of the regulation itself so those lawyers and judges who’ve been ignoring you can’t do that any longer.

Well, that’s exactly what the FDA’s finally been forced to do in product liability litigation.

We’ve blogged before about 21 C.F.R. §314.70(c)(6)(iii) and what the FDA said in the Federal Register back in 1982 when it drafted it. This is the regulation which creates an exception from prior FDA approval for new or stronger drug warnings (there are similar exceptions for devices and biologics, which the FDA’s new proposal covers, but drugs are the biggie). This regulation currently reads:

(6) The agency may designate a category of changes for the purpose of providing that, in the case of a change in such category, the holder of an approved application may commence distribution of the drug product involved upon receipt by the agency of a supplement for the change. These changes include, but are not limited to:

****

(iii) Changes in the labeling. . .to accomplish any of the following:

(A) To add or strengthen a contraindication, warning, precaution, or adverse reaction....
As we pointed out last April, the 1982 Federal Register explanation for this provision said – and not just once – that this exception was added to cover situations involving “newly discovered risks” and “new information about the safe use of a drug product.” 47 Fed. Reg. 46622, 46623, 46635 (FDA Oct. 19, 1982).

That’s precisely what the FDA’s new proposal (now officially in the Federal Register at 73 Fed. Reg. 2848 (FDA Jan. 16, 2008)) for revising §314.70(c) makes clear:

FDA proposed what is essentially the current CBE procedure in 1982. When proposed, the agency made clear that CBE supplements were intended to apply only if the sponsor became aware of newly discovered safety information that was appropriate for inclusion in the labeling for the product. Indeed, in the preamble to the proposed rule for the CBE provision for drugs, the agency stated [passage quoted in our prior blog post omitted]. In that preamble, the agency also emphasized that the CBE procedure was a limited exception to the general requirement of prior FDA approval for a labeling change: [passage quoted in our prior blog post omitted]
73 Fed. Reg. at 2849-50 (emphasis added).

The FDA even found a passage from the Final Rule adopting §314.70(c)(6)(iii) the we, frankly, missed in our prior post (but then we were just blogging, not writing anything we get paid to do). The Agency points out that back in 1985, when it finally approved this exception, it reiterated that it was intended for newly discovered information:

Similarly, in the preamble to the final rule, FDA again emphasized that CBE supplements were intended as a narrow exception to the general rule that labeling changes require FDA’s prior approval:

Drug labeling serves as the standard under which FDA determines whether a product is safe and effective. Substantive changes in labeling * * * are more likely than other changes to affect the agency’s previous conclusions about the safety and effectiveness of the drug. Thus, they are appropriately approved by FDA in advance, unless they relate to important safety information, like a new contraindication or warning, that should be immediately conveyed to the user.
73 Fed. Reg. at 2850 (quoting 50 Fed. Reg. 7452–01, 7470 (FDA Feb. 22, 1985)) (emphasis added).

The problem with §314.70(c)(6)(iii) is that the agency’s limited purpose wasn’t expressly stated in the 1980s text of the regulation itself. That wasn’t much of a problem for many years until along came preemption in the wake of landmark Supreme Court cases in Cipollone v. Liggett Group, Inc., 505 U.S. 504 (1992) (holding that state common law torts were something that was subject to preemption), Medtronic, Inc. v. Lohr, 518 U.S. 470 (1996) (repeating this holding in the context of the FDCA), and especially Buckman Co. v. Plaintiffs’ Legal Committee, 531 U.S. 341 (2001) (recognizing implied conflict preemption in the context of the FDCA).

As we’ve posted before, preemption is a really powerful defense in prescription drug product liability litigation - more powerful than any other. Read the prior post, but in one sentence (OK, two), preemption is more powerful because when it applies, it applies to every case involving that product, no matter how strong any particular plaintiff’s case might be on its other “merits.” The plaintiff could have the worst injuries, the most sympathetic story, and the most persuasive expert on medical causation and none of that would matter – if the claim’s preempted, case dismissed.

You can’t expect the plaintiffs’ side to take the advent of preemption lying down. They’re too smart and too persistent for that - and they make too much money from this type of litigation. And they sure didn’t. They developed a whole bunch of anti-preemption arguments in prescription drug litigation, but their best (at least the one that more courts have bought than any other) argument relies upon §314.70(c)(6)(iii). There’s no conflict with FDA regulation, this argument goes, because under that regulation, the defendant pharmaceutical company could always add or strengthen its warning without prior FDA approval – and state law required that in the particular case.

On Westlaw (that’s a computerized service that collects legal opinions), there are 43 cases citing §314.70(c)(6)(iii). Tellingly, there are no product liability citations – none – to this exception before Cipollone was decided in 1992). Many, probably most, of those cases don’t involve new or materially different information. Thus they’re not cases the FDA contemplated back in 1983-85 would be subject to this tiny subsection of a subsection. Most of the cases don’t even acknowledge that any limitation to newly discovered or different information exists, although as we discussed in April, a few do.

The plaintiffs argue that this exception wholly swallows the erstwhile rule that drug labeling changes are subject FDA pre-approval. All the rest of this (typically) long and involved regulation doesn’t matter a hill of beans. And a surprising number of courts are quite content to cede the regulatory field to the plaintiffs’ lawyers. In particular, courts have accepted this §314.70(c)(6)(iii) argument and ruled that pharmaceutical defendants should have unilaterally strengthened suicide warnings for antidepressants – despite the FDA having evaluated the evidence of this so-called “risk” at least a half-dozen times and each time concluding (as recently as late 2007) that there’s no scientific basis for including a suicide warning. Of course, the underlying condition these drugs treat, depression, is a notorious cause of suicide. See McNellis v. Pfizer, Inc., 2006 WL 2819046, at *2,4 (D.N.J. Sept. 29, 2006) (the companion case to Colacicco); Jackson v. Pfizer, Inc., 432 F. Supp.2d 964, 968 (D. Neb. 2006); Laisure-Radke v. Par Pharmaceutical, Inc., 2006 WL 901657, at *4-5 (W.D. Wash. Mar. 29, 2006); Witczak v. Pfizer, Inc., 377 F. Supp.2d 726, 729-30 (D. Minn. 2005); Cartwright v. Pfizer, Inc., 369 F. Supp.2d 876, 882-83 (E.D. Tex. 2005); Zikis v. Pfizer Inc., 2005 WL 3019409, at *3-4 (N.D. Ill. Nov. 8, 2005); Motus v. Pfizer, Inc., 127 F. Supp.2d 1085, 1093-94 (C.D. Cal. 2000); cf. Colacicco v. Apotex, Inc., 432 F. Supp.2d 514, 523, 527-28 (E.D. Pa. 2006) (rejecting §314.70(c)(6)(iii) argument in antidepressant case and finding preemption). As we’ve pointed out, these suicide cases have repeatedly been the subject of FDA amicus briefs supporting preemption.

Not only that, the Levine case that’s currently pending before the Supreme Court (let’s see what tomorrow will bring) is another example of the misuse of §314.70(c)(6)(iii). There, the Vermont Supreme Court relied upon this regulation to reject preemption, Levine v. Wyeth, 2006 WL 3041078, at ¶¶13-14, 19 (Vt. Oct. 27, 2006), even though it discussed at length (and poo-pooed) the FDA’s previous decision to reject additional warnings concerning the particular risk involved:

Defendant argues that the instruction reflected the FDA’s opinion not only that a stronger warning was unnecessary, but also that it would have harmed patients by eliminating IV push as an option for administering Phenergan. The record does not support this interpretation. Defendant has provided a number of letters exchanged by the FDA and defendant regarding Phenergan’s label, but these letters do not indicate the FDA’s opinion of the value of IV-push administration. Neither the letters nor any other evidence presented to the jury indicated that the FDA wished to preserve the use of IV push as a method of administering Phenergan. Nor can we infer such concern from the agency’s instruction to “[r]etain current verbiage” instead of adopting the proposed warning.. . . . With respect to IV administration, the original label read, “When administering any irritant drug intravenously it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be functioning satisfactorily,” while the proposed label stated, “[i]njection through a properly running intravenous infusion may enhance the possibility of detecting arterial placement. In addition, this results in delivery of a lower concentration of any arteriolar irritant.” Simply stated, the proposed warning was different, but not stronger. It was also no longer or more prominent than the original warning, so it could not have raised a concern that it might overshadow other warnings on the label or drive doctors away from prescribing the drug. There is no evidence that the FDA intended to prohibit defendant from strengthening the Phenergan label pursuant to §314.70(c).
Levine ¶23 (emphasis added). Thus, the FDA had already undisputedly evaluated the particular risk in Levine. There was no suggestion of any “new” information being involved, so the Levine court’s reliance upon §314.70(c)(6)(iii) was entirely beyond how the FDA had contemplated that exception would be used when it wrote the original regulation

Indeed, the Solicitor General hastened to inform the Supreme Court about the FDA’s proposal to amend §314.70(c)(6)(iii) the day it was published in the Federal Register - not just in Levine, but in Riegel and Kent as well.

Three things are thus clear about §314.70(c)(6)(iii) and preemption: (1) when it adopted this regulation, FDA intended it as a limited, emergency exception to the general rule of Agency pre-approval of changes to prescription drug labeling; (2) since preemption became an issue in prescription drug product liability litigation, the regulation has repeatedly been cited by courts as applying far more broadly than the FDA intended, and (3) the FDA has repeatedly tried, through amicus briefs and the 2006 preemption preamble, to inform courts of the limited scope of the regulation, with only mixed success.

In light of all this, it’s no surprise at all to us that the Agency would seek to amend the offending regulation to confine it to the narrow scope for which it’s always been intended. In fact, we're more of the view “what took you guys so long?”

OK, but tell us how the FDA’s proposal “assists preemption.”

No problem. The plaintiffs’ argument is that, since manufacturers are supposedly “free” to change their labels without prior FDA approval, there’s no conflict with state law holding them liable for not doing what §314.70(c)(6)(iii) – they claim – allows.

Thus, the less discretion manufacturers have under this regulation – the fewer situations in which pre-approval changes are permitted – the fewer situations in which the plaintiffs can make their most successful anti-preemption argument, because the key regulation doesn’t apply. In particular, preemption applies both in Levine and in the anti-depressant suicidality cases, because neither of those litigations involve new or materially different risks of the sort to which the amended, more limited, version of the regulation would be restricted.

That the amended regulation would apply to fewer prescription drug situations means that implied conflict preemption conversely would apply to more situations. Defendants, being able to use their most powerful defense in more situations, would win more cases.

That’s why we complained about the misuse of §314.70(c)(6)(iii) last April, and that’s why we, as lawyers who represent defendants in this type of case, are frankly thrilled with the FDA’s proposal. For exactly the same reason, that’s why the plaintiffs’ lobbyists and supporters in Washington (such as ATLA) are apoplectic. Our side wins more. Their side loses more. It’s as simple as that.

So what exactly is the Agency proposing?

Two things, basically. First and foremost it’s putting explicit language in the regulation expressing the limited circumstances in which prescription drug manufacturers would be permitted to use “Changes Being Effected” supplements to change labeling without the FDA saying in advance that the changes are OK. New §314.70(c)(6)(iii) will read:

(iii) Changes in the labeling to reflect newly acquired information. . . to accomplish any of the following:

(A) To add or strengthen a contraindication, warning, precaution, or adverse reaction for which the evidence of a causal association satisfies the standard for inclusion in the labeling under 201.57(c) of this chapter. . . .
(Emphasis added) As the FDA says, the purpose of these amendments is to codify its “longstanding position” that was reflected in the Agency’s 1980s Federal Register statements, and the amicus briefs that it’s been filing since the anti-depressant cases brought the plaintiffs’ improperly expansive reading of the original regulation to the Agency’s attention. The FDA explicitly states the CBE procedure must be a “narrow exception” to preserve its overall authority over labeling. 73 Fed. Reg. at 2849.

FDA believes it necessary to amend its regulations to make explicit the agency’s understanding that a sponsor may utilize the limited CBE provisions only to reflect newly acquired safety information. FDA intends to consider information ‘‘newly acquired’’ if it consists of data, analyses, or other information not previously submitted to the agency, or submitted within a reasonable time period prior to the CBE supplement, that provides novel information about the product, such as a risk that is different in type or severity than previously known risks about the product.
Id. at 2850 (emphasis original). Newly acquired information is not just about risks “not previously submitted” but also includes “adverse events of a. . .greater severity or frequency than previously included in submissions to FDA” (which can include new statistical analyses, such as meta-analysis). Id. at 2850.

The Agency pulls no punches. Rather it says about as clearly as it’s possible to do that this proposal will expand the scope of implied preemption in product liability cases involving prescription drugs:

[T]o the extent that state law would require a sponsor to add information to the labeling for an approved drug or biologic without advance FDA approval based on information or data as to risks that are similar in type or severity to those previously submitted to the FDA, or based on information or data that does not provide sufficient evidence of a causal association with the product, such a state requirement would conflict with federal law.
Id. at 2852 (emphasis added). There will be implied preemption in prescription drug cases because “[i]n such a situation, it would be impossible to market a product in compliance with both federal and state law, and the state law would stand as an obstacle to the accomplishment and execution of the full purposes and objectives of Congress.” Id. There would also be express preemption in medical device cases because “such a state law requirement relating to a medical device would constitute a requirement that is different from, or in addition to, a federal requirement applicable to the device.” Id.

The second clarification the FDA wants to make to §314.70(c)(6)(iii) would specify that the new or materially different evidence of risk must meet strong standards of scientific validity to justify bypassing FDA pre-approval. That’s what the amended regulation’s reference to §201.57(c) is all about.

Plaintiffs have argued in some cases (such as the Colacicco appeal) that the CBE procedure is available even for information that meets the very low standard set by 21 C.F.R. §201.80(e) – “reasonable evidence of an association. . . . A causal relationship need not have been proved.”

The FDA’s new proposal says that’s wrong, too. Only strong information that meets the standards for label changes under §201.57(c) is eligible, because only strong information warrants the extraordinary step of dispensing with Agency pre-approval. If it’s anything less certain, then there’s not any emergency justifying resort to CBE procedures:

FDA proposes to clarify that a CBE supplement may be used only to implement labeling changes regarding contraindications, warnings, precautions, or adverse reactions in circumstances when there is sufficient evidence of a causal association. . . . The rule provides that not all adverse events observed during use of a drug are eligible for inclusion in labeling, but rather ‘only those adverse events for which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event.
73 Fed. Reg. at 2850 (emphasis added).

Under the referenced §201.57, this standard would vary (as it does for normal label changes) depending on whether a particular modification is to a warning/precaution, to an adverse reaction, or to a contraindication. Id. at 2850-51. Here the FDA’s proposal gets rather detailed and technical, but if the distinctions are important to you, read the entire FDA proposal. The Agency does make it quite clear is that the lower standard of §201.80 does not apply:
Section 201.80 sets forth similar, although not identical, criteria. . . . Because §201.57 represents the agency’s most recent consideration of this topic, FDA proposes that, if a sponsor intends to utilize the limited CBE procedure set forth in §314.70(c)(6)(iii) or §601.12(f) [for biologics], it must possess information regarding causation sufficient to satisfy the criteria set forth in §201.57(c), regardless of whether the drug or biologic is subject to the labeling requirements of §201.57 or §201.80.
Id. at 2851.

It’s also significant that the FDA “does not consider this amendment to be a substantive change.” Id. Thus, the FDA’s historical analysis of §314.70(c)(6)(iii), and of the CBE procedure generally, applies to litigation that’s already in progress in which plaintiffs are attempting to misconstrue the regulation.

As with all FDA “proposed rules” (that’s the applicable administrative jargon), there is a notice and comment period of 60 days – meaning the deadline for public comment is March 17, 2008. The proposal provides instructions for submitting comments. We encourage all our defense-oriented readers to submit favorable comments, since ATLA is sure as hell going to oppose. We might even be submitting comments of our own.

2 comments:

Anonymous said...

The FDA is Congress's whipping boy.
The Drug an Device law is tap dancing around the real issues.
In 1962 during Kennedy as president, The Congress omitted any remedy for a defective prescription drug, No product Liability, No Federal Law or Statue Federal or State. Therefor Congress put up a shield to protect the prescription Drug Companies and put the public at risk. All the CBE's and all the rules and regulations have no meaning when it comes to killing and injury of amy person if there is No Law. Congress preempted the FDA Act when they amended the FDA to include FDCA act in 1962. Public Law as amended by Congress. I have a RICO Complaint filed in June 2007 that includes 3 CEO's and Merck & Co. Inc. I am a Vioxx Survivor and I have stated that Merck did knowinly and willingly did in fact kill 88,000 and injured with heart attachs and strokes 149,000, proof is they thought they would never get caught. Hiding behind the 5th amendment and stating they did no wrong. well killing human beings is a crime and even though they can not be prosecuted under the Product liability law. or Tort they can be prosecuted under a RICO. Pharma needs t be held accountable for the injury and taking of livss even if it is neglect or intentional. Check it out. the RICO Complaint is in the 5th Circuit Court of Appeals.

Anonymous said...

haha. I like how you left off the bold under lining from the words "some basis to" before the part that says "believe there is a causal association."

That cheeky little move right there says it all. Must be nice to not have a conscience.