Thursday, April 05, 2007

"Changes Being Effected" Labeling and Novelty

When you argue implied preemption as much as we do in prescription drug product liability litigation cases, you get to know the plaintiffs’ come back arguments in your sleep. Chief among them is that because the FDA’s so-called “changes being effected” (“CBE”) regulation, 21 C.F.R. §314.70(c), allows drug manufacturers to strengthen safety language without prior FDA approval.

The argument is that, because CBE warning changes can be made without prior FDA approval, there’s no conflict between the FDA’s regulatory scheme and a tort claim demanding an unapproved labeling change. E.g., McNellis v. Pfizer, Inc., 2006 WL 2819046, at *7 (D.N.J. Sep. 29, 2006). This argument typically ignores regulatory practice, the regulation’s requirement that any CBE warning changes be simultaneously submitted to the FDA, and that the FDA has ultimate authority to approve or reject the labeling change. E.g., Sykes v. Glaxo-SmithKline, 2007 WL 957337, at *18 (E.D. Pa. Mar. 28, 2007) (“A manufacturer may, under FDA regulations, strengthen a labeling warning, but in practice manufacturers typically consult with FDA before doing so to avoid implementing labeling changes with which the agency ultimately might disagree”).

Nevertheless, because a lot of judges dislike preemption for one reason or another, the CBE argument has prevailed on a number of occasions recently. E.g., Levine v. Wyeth, 2006 Vt. Lexis 306, at *12-13 (Vt. Oct. 27, 2006); McNellis, supra; Laisure-Radke v. Par Pharmaceutical, Inc., 2006 WL 901657, at *4 (W.D. Wash. Mar. 29, 2006); Caraker v. Sandoz Pharmaceuticals Corp., 172 F. Supp.2d 1018, 1033-34 (S.D. Ill. 2001). In giving credence to this argument, courts have stretched a small regulatory exception for emergency situations beyond recognition, and use it to swallow the general rule – that warnings on FDA-regulatory products are subject to prior FDA review and approval. The result is that the intensive FDA review process, in product liability litigation, becomes merely a “minimum” standard that judges applying state law are free to ignore at their pleasure.

There are a lot of objections that can be – and have been – made to this state of affairs. We’re focusing on just one here, and that’s how §314.70(c) has been improperly applied to non-emergent situations. There are, after all, a lot of drug risks that have been reported in the literature for many years. Drug manufacturers have to keep up with known risks on a routine basis, and their labeling reflects these risks. As a result there is often extensive regulatory history as the manufacturer and the FDA consult about exactly what kind of “precaution,” “warning,” “contraindication” or other labeling a particular risk warrants based upon the current state of medical knowledge.

There’s simply no basis for applying §314.70(c) in opposition to preemption in a case involving a previously known risk where the plaintiff’s claim amounts to a disagreement about whether existing risk information warranted a more emphatic warning than what the FDA has approved. The provision for CBE labeling is supposed to address a very specific situation – that of newly discovered and scientifically significant evidence. Such evidence may either require the addition or strengthening of a warning, or a change in dosage or administration. §314.70(c)(6)(iii) (A, C). CBEs are solely interim, emergency steps. “[T]he determination whether labeling revisions are necessary is, in the end, squarely and solely FDA’s.” 71 Fed. Reg. 3922, 3934 (FDA Jan. 24, 2006). Section 314.70 was adopted by the FDA in essentially its present form in 1982. The FDA specified that CBE labeling changes were intended to streamline procedures for “newly discovered” drug risks:
[S]ome information, although still the subject of a supplement, would no longer require agency preclearance. These supplements would describe changes placed into effect to correct concerns about newly discovered risks from the use of the drug.

47 Fed. Reg. 46622, 46623 (FDA Oct. 19, 1982) (emphasis added). Later in the same document, the FDA reiterated that CBEs are intended to speed up dissemination of “new” safety information:
Although most changes in labeling would require the applicant to submit a supplement and obtain FDA approval before making a change, the following changes in labeling, which would make available important new information about the safe use of a drug product, could be made if the applicant submits a supplement when the change is made: Changes that add or strengthen a contraindication, warning, precaution, or statement about an adverse reaction, drug abuse, dependence, or overdosage, or any other instruction about dosage and administration that is intended to improve the safe use of the product.
Id. at 46635 (emphasis added).

Some of the more nuanced judicial discussions of §314.70 likewise recognize that the regulation doesn’t open the door broadly to any sort of unapproved label “strengthening” that a plaintiff might advocate in a particular case. Weiss v. Fujisawa Pharmaceutical Co., 464 F. Supp.2d 666, 675 (E.D. Ky. 2006) (under §314.07 “a drug manufacturer may warn patients and healthcare providers should they discover new evidence of a particular risk following the approval of the original label); Perry v. Novartis Pharmaceuticals Corp., 456 F. Supp.2d 678, 685-86 (E.D. Pa. 2006) (“This particular regulation was promulgated precisely to allow drug-makers to quickly strengthen label warnings when evidence of new side effects are discovered”). Other cases recognize the limitation – and inconsistently proceed to ignore it. Witczak v. Pfizer, Inc., 377 F. Supp.2d 726, 729 (D. Minn. 2005) (same as Perry); Zikis v. Pfizer Inc., 2005 WL 3019409, at *3 (N.D.Ill. Nov. 8, 2005) (§314.70 “allows for an amendment to a label without extended delay when a drug manufacturer learns of new dangerous side effects”).

While the “new information” trigger to §314.70 is unfortunately not express within the regulation itself, it is explained repeatedly in the both the regulatory history and in the more perceptive case law governing the rule. Beyond that, recognition of the limited role that the Agency has always envisioned for CBE warning revisions harmonizes this regulation with the FDA’s view of the circumstances under which preemption is appropriate. Fully three of the FDA’s six categories of preempted cases deal with situations where the risk at issue is not “newly discovered”:

(4) claims that a drug sponsor breached an obligation to warn by failing to include a statement in labeling or in advertising, the substance of which had been proposed to FDA for inclusion in labeling, if that statement was not required by FDA at the time plaintiff claims the sponsor had an obligation to warn. . .; (5) claims that a drug sponsor breached an obligation to warn by failing to include in labeling or in advertising a statement the substance of which FDA has prohibited in labeling or advertising; and (6) claims that a drug’s sponsor breached an obligation to plaintiff by making statements that FDA approved for inclusion in the drug’s label.

71 Fed. Reg. at 3936 (emphasis added).

The FDA is rightly concerned with tort litigation that seeks to overturn regulatory decisions the Agency has already made by: (1) declining to require something, (2) prohibiting something, or (3) mandating something. This concern is simply the flip side of how the CBE regulation has always been supposed to function. By definition, none of these three preemptive situations can involve “newly discovered” risks. Necessarily the information that is in dispute has already been submitted to, and passed upon by, the FDA. The FDA's primary and ongoing responsibility for the content of prescription drug labeling simply cannot be reconciled with case law that assumes that manufacturers can make whatever “strengthening” changes to their labeling they want, whenever they want, and for as long as they want after that labeling has already been approved by the FDA.

Cases that isolate §314.70 from everything else for which the FDA has responsibility forget that “[s]tatutory construction is a holistic endeavor.” U.S. National Bank v. Independent Insurance Agents of America, Inc., 508 U.S. 439, 455 (1993). What a statute or regulation means is often “clarified” by its context in an overall scheme that rules out other “permissible meanings”:

Statutory construction. . .is a holistic endeavor. A provision that may seem ambiguous in isolation is often clarified by the remainder of the statutory scheme. . .because only one of the permissible meanings produces a substantive effect that is compatible with the rest of the law.

United Savings Ass’n v. Timbers of Inwood Forest Associates, Ltd., 484 U.S. 365, 371 (1988).

Thus, where the information in question is not “newly discovered,” but rather has already been addressed in existing drug labeling that has been approved by the FDA, courts should let the FDA’s decision stand and not misconstrue §314.70 to apply to this situation. A science-based FDA determination based upon a mix of technical information that has not changed significantly is entitled to deference from the courts. E.g., Weinberger v. Bentex Pharmaceuticals, Inc., 412 U.S. 645, 653-54 (1973); Alpharma, Inc. v. Leavitt, 460 F.3d 1, 6 (D.C. Cir. 2006); Nutraceutical Corp. v. Von Eschenbach, 459 F.3d 1033, 1043 (10th Cir. 2006); Mylan Pharmaceuticals, Inc. v. FDA, 454 F.3d 270, 275-76 (4th Cir. 2006); NVE, Inc. v. Department of HHS, 436 F.3d 182, 196 (3d Cir. 2006).

1 comment:

International Regulatory Affairs said...

Thanks for this wonderful post...................