We were recently asked the question, “are failure to contraindicate claims preempted?” Our immediate response was, “How could they not be”? However, it’s not helpful to answer a question with a question, and as with all things preemption, matters are not as simple as they might seem. Therefore, we thought we’d explore this issue in more depth.

We discussed failure to contraindicate claims several times in the run-up to Wyeth v. Levine, 555 U.S. 555 (2009). We believed – and still do – that Levine was tried to the jury on a claim that the defendant should have contraindicated the particular use of the drug involved in that case. It didn’t ultimately turn out that way. Rather, in Levine, the Supreme Court went through contortions specifically to avoid having to decide a “failure to contraindicate” claim:

[Plaintiff] also offered evidence that the [FDA-approved use] should be contraindicated and that [the drug] should never be administered [that way]. Perhaps for this reason, the dissent incorrectly assumes that the state-law duty at issue is the duty to contraindicate. . . . But, as the Vermont Supreme Court explained, the jury verdict . . . did not mandate a particular replacement warning, nor did it require contraindicating [the use]. . . . We therefore need not decide whether a state rule proscribing [the FDA-approved use] would be pre-empted.

555 U.S. at 564-65. Heck, even the plaintiffs’ counsel in Levine conceded that a failure-to-contraindicate “would be preempted” where the FDA “concluded that it should not be” contraindicated. Levine argument transcript at 32-33; see id. at 39-40.

Levine thus did not allow failure to contraindicate claims – rather it changed the facts of the case to avoid doing that, while still reaching an anti-preemption result. Pretty obviously, the anti-preemption justices in Levine could not muster a majority that would permit state tort law claims that sought to ban FDA-approved uses. Compare the result in Levine to the extensive preemption recognized in Riegel v. Medtronic, Inc., 552 U.S. 312 (2008), where the Court did recognize the presence of a contraindicated use. Id. at 320 (device used in a patient’s “heavily calcified” arteries; “the device’s labeling stated that use was contraindicated for patients with diffuse or calcified stenosis”). Among Riegel’s preemption holdings was that the plaintiff’s warning claims were preempted. Id. at 329 (holding “the MDA would pre-empt a jury determination that the FDA-approved labeling for [the device] violated a state common-law requirement for additional warnings”).

The regulatory background for a contraindication is much more stringent than for warnings and other types of labeling. The FDA’s strict prerequisites for contraindications are at 21 C.F.R. §201.57(d). That regulation requires: (1) a contraindication must relate to a “known hazard” and (2) due to that hazard “the risk of use clearly outweighs any possible benefit.”

Further reflecting that stringency, while the FDA’s changes-being-effected (“CBE”) regulation used to include “contraindications” broadly as something subject to unilateral modification, that’s no longer so. As discussed in excruciating detail below, the FDA amended the relevant regulation in 2006, and now most contraindications in fact are subject to an express exception in the CBE regulation that requires prior FDA approval. Thus, the CBE regulation should no longer an obstacle to finding failure to contraindicate claims preempted. For almost every prescription drug that hasn’t gone generic, arguing that failure to contraindicate claims aren’t preempted on the basis of the CBE regulation is simply bogus, since that regulation is inapplicable.

A failure to contraindicate claim is inherently in conflict with FDA regulatory authority, since it would allow liability based on the defendant’s failure to contraindicate a use that the FDA had looked at and said was okay. Once the FDA says “you can do X,” that regulatory result is in absolute conflict with a state-law cause of action predicated on a theory that “you can’t do X.” This kind of state-law infringement on FDA powers has been preempted under the FDCA for over 100 years. See McDermott v. Wisconsin, 228 U.S. 115, 137 (1913) (finding conflict preemption where state law “forb[ade] all labels other than the one it prescribed,” including the FDA-approved label).

So this direct conflict is one preemption argument that applies against a failure to contraindicate claim. The FDA approves/clears drugs and medical devices for each “intended use.” 21 C.F.R. §§201.128, 801.4804.1. A failure to contraindicate claim seeks to prohibit an FDA-allowed intended use. Thus, such claims are really a species of “stop selling” claim of the sort that the Supreme Court held were impliedly preempted in Mutual Pharmaceutical Co. v. Bartlett, 133 S.Ct. 2466 (2013):

The Court of Appeals reasoned that [defendant] could escape the impossibility of complying with both its federal- and state-law duties by “choos[ing] not to make [sulindac] at all.” We reject this “stop-selling” rationale as incompatible with our pre-emption jurisprudence. Our pre-emption cases presume that an actor seeking to satisfy both his federal- and state-law obligations is not required to cease acting altogether in order to avoid liability. Indeed, if the option of ceasing to act defeated a claim of impossibility, impossibility pre-emption would be all but meaningless.

Id. at 2477 (citations and quotation marks omitted). Courts have recognized that disguised stop-selling claims are likewise preempted under Bartlett. Thus, as we discussed here, in Yates v. Ortho-McNeil Pharmaceuticals, Inc., 808 F.3d 281, 300 (6th Cir. 2015); Utts v. Bristol-Myers Squibb Co., ___ F. Supp.3d ___, 2016 WL 7429449, at *11 (S.D.N.Y. Dec. 23, 2016); and Brazil v. Janssen Research & Development LLC, 196 F. Supp.3d 1351, 1364 (N.D. Ga. 2016), never-start selling claims based on allegations that the defendant should never have submitted the product to the FDA were all held preempted as “stop-selling” claims.

Failure to contraindicate allegations satisfy our rule of thumb for identifying disguised stop-selling claims. We look at the learned intermediary rule and causation. Would the claim in question allow the plaintiff to argue that the actions of the “learned intermediary” – the prescribing physician/treating surgeon – are irrelevant to a causation determination because the physician should never have been allowed to prescribe/use the product on the plaintiff in the first place? If yes, then the claim is a disguised, and preempted, stop-selling claim. The fraud-on-the-FDA claims in Buckman, the stop-selling claims in Bartlett, the Yates claims that a different design should have been submitted to the FDA in the first place all share this characteristic, as do failure to contraindicate claims.

This is our preferred route to preemption of failure-to-contraindicate claims. There is simply an inherent conflict between the FDA’s regulatory authority to decide what products/”intended uses” are able to be marketed in the United States and state-law claims that would allow liability for failure to contraindicate a use that the FDA has approved.

There is also a more technical preemption argument – alluded to earlier, when we mentioned the CBE regulation − at least with respect to prescription drugs and biologicals. As discussed in Levine, 555 U.S. at 568-72, PLIVA, Inc. v. Mensing, 564 U.S. 604, 614-15 (2011), and by us here, the key to implied preemption is what we call the “independence principle.” As concisely stated in Mensing:

[W]hen a party cannot satisfy its state duties without the Federal Government’s special permission and assistance, which is dependent on the exercise of judgment by a federal agency, that party cannot independently satisfy those state duties for pre-emption purposes.

564 U.S. at 623-24. The branded manufacturer in Levine, but not the generic manufacturer in Mensing, could have revised aspects of its label independently – however temporarily − by using the the FDA’s“changes-being-effected” (“CBE”) process. Back when plaintiffs in Mensing and Levine alleged that labels should be modified, “[t]he CBE process permit[ted] drug manufacturers to ‘add or strengthen a contraindication, warning, [or] precaution.’” Mensing, at 614 (citing 21 C.F.R. §314.70(c)(6)(iii)(A) (2006)).

However, neither Levine (2000 injury) nor Mensing (2001 & 2002 injuries) interpreted the current version of the FDA’s CBE regulation. Effective June 30, 2006 – that regulation was amended by the Physician Labeling Rule (“PLR”) so that 21 C.F.R. §314.70(c)(6)(iii) now reads:

Changes in the labeling, except for changes to the information required in §201.57(a) of this chapter (which must be made pursuant to paragraph (b)(2)(v)(C) of this section), to accomplish any of the following:

FDA, “Requirements on Content and Format of Labeling for Human Prescription Drug & Biological Products, 71 Fed. Reg. 3922, 3997 (Jan. 26, 2006) (reflecting amended language) (emphasis added). See id. at 3922 (stating effective date). Exactly this language is in the current version of 21 C.F.R. §314.70(c)(6)(iii) in the United States Code.

That means that the broad applicability of the CBE regulation to “contraindications” alluded to in Mensing and Levine no longer exists.

Since the mid-2006 PLR revision, there has been an express exception to the CBE rule for “changes to information required in” 21 C.F.R. §201.57(a), which is the regulation that requires inclusion of a “Highlights” section to prescription drug labeling. No “Highlights” section even existed under the format for prescription drug labeling that governed the period of time at issue in Levine or Mensing.

Changes to Highlights information thus cannot be made unilaterally under the CBE regulation. Rather 21 C.F.R. §314.70(b)(2)(v)(C) applies. That section concerns “major changes” for which “[a] supplement must be submitted” to the FDA. Id. §§314.70(b), 314.70(b)(1). As one might expect, all drug “contraindications” must be included in the Highlights section:

Highlights of prescribing information. The following information must appear in all prescription drug labeling: . . . (9) Contraindications. A concise statement of each of the product’s contraindications. . . .

21 C.F.R. §201.57(a)(9) (emphasis added). Highlights must now be included for any prescription drug approved by the FDA after June 30, 2001. See 21 C.F.R. §201.56(c) (setting out staggered compliance schedule, completed in 2013, for drugs approved between that date and June 30, 2006, when all new drug applications must contain labeling highlights).

Thus, while the old CBE regulation, considered by the Supreme Court in Levine and Mensing, included “contraindications” generally as types of warnings that could be modified/strengthened unilaterally, now contraindications (and anything else that must be included in PLR Highlights) may not be unilaterally added to the labeling for any drug approved after June 30, 2001. The Highlights need not present all “Warnings” and “Precautions” contained in the labeling − only a “concise summary of the most clinically significant” safety concerns is required. 21 C.F.R. §201.57(a)(10). Contraindications, however, are different. Section 201.57(a)(9) mandates that “each” contraindication be included in the Highlights section for drug labeling. CFR § 201.57(c)(6).

The FDA discussed the Highlights section and the CBE process further in a 2013 guidance document:

Changes to Highlights through a CBE supplement: With minor exceptions, changes to Highlights require a prior approval supplement (§§314.70 and 601.12). If the labeling is already approved in the PLR format and the proposed change(s) qualify for a CBE supplement under §§314.70(c) and 601.12(f), a prior approval supplement is not needed as long as the change does not warrant inclusion in Highlights (e.g., addition of an adverse reaction to the ADVERSE REACTIONS section in the FPI). If, in the opinion of the applicant, the new information warrants inclusion in Highlights or will be listed under Recent Major Changes in Highlights (i.e., a change to the BOXED WARNING, CONTRAINDICATIONS, OR WARNINGS AND PRECAUTIONS sections), the applicant should notify the appropriate review division about the proposed change to the labeling. The review division may permit changes to Highlights through a CBE supplement after consideration of the new information.

FDA, Guidance for Industry, Labeling for Human Prescription Drug & Biological Products − Implementing the PLR Content & Format Requirements, 2013 WL 10904638, at *21 (Feb. 2013) (emphasis added).

Putting all this regulatory material together in more easily comprehensible form, the upshot is that failure to contraindicate claims should now be preempted by reason of impossibility under the Mensing/Bartlett “independence principle” for any prescription drug (or biological) approved by the FDA since mid-2001. Since all contraindications must be included in Highlights, and all changes to Highlights require prior FDA review and approval – either through a Prior Approval Supplement (“PAS”) or, as noted in the above FDA PLR Guidance, through a CBE supplement “after” FDA has consider the new information and permitted the change through a CBE supplement – contraindications can no longer be changed unilaterally via the CBE process.

So far, Highlights haven’t received a lot of attention in preemption cases. We recently discussed the first case we found on this point, Blackburn v. Shire US, Inc., 2017 WL 1833524 (N.D. Ala. May 8, 2017), which did not involve any allegations concerning contraindications. Blackburn held:

[I]n almost all instances, any change to the Highlights section of an approved drug’s label requires FDA approval. Again, in circumstances such as these, a private party’s claim is only preempted if the drug manufacturer was not able to act independently under federal law to do what state law requires. That is, preemption exists “when a party cannot satisfy its state duties without the Federal Government’s special permission and assistance.” [Mensing], 564 U.S. at 623-24. Such assistance “is dependent on the exercise of judgment by a federal agency,” and as such “that party cannot independently satisfy those state duties for preemption purposes.” Id. at 624. Accordingly, when sufficient newly acquired information exists in order to support a label change under the CBE process, as has been plausibly pled here, the claim is not preempted.

However, the same cannot be said with respect to Plaintiff’s assertion that a change to the Highlights section would be permitted here. Where a private party seeks a label change which requires FDA approval, such as a change to the Highlights section, impossibility preemption exists. . . . The “impossibility” inquiry turns on a private party’s ability to act independently. It is of no consequence that the FDA may have allowed a change to the Highlights section of [the drug]. Because Defendants could not have independently changed the Highlights section of [the drug] in order to conform to state law, any argument that begins with the theory that Defendants could (or should) have changed the Highlights section of [the drug’s] label ends in preemption.

Id. at *5-6 (emphasis added). The court rejected the plaintiff’s attempt to avoid preemption of changes to Highlights by arguing that the defendant could have “sought expedited FDA approval of the Highlights section change or asked the FDA to waive such an approval requirement by submitting a written waiver request to the FDA.” Id. at *6. The availability of these options doesn’t matter for preemption purposes, since neither allows the defendant to make a change to its label independently, which is what is necessary to avoid preemption under Levine, Mensing, and Bartlett.

Finally, turning away from legal issues, contraindications also work differently in medical practice, where physicians often view them as outright bans. For a physician to proceed in the face of a labeled contraindication invites malpractice claims, perhaps even punitive damages, if anything goes wrong. Contraindications thus tend to replace, rather than supplement, the usual physician balancing of risks and benefits.

Were juries allowed to impose contraindications that do not meet the FDA’s strict standards, patients and physicians would be deprived of drug and device uses in situations where, from the agency’s perspective, risk does not outweigh benefit. The dynamics of mass tort litigation only exacerbate matters as a jury-imposed contraindication-based verdict in one state becomes precedent seeking the same effective ban nationwide – particularly as the FDA does not allow product labeling to vary by state. Thus, particularly pro-plaintiff juries in certain locales would impose Gresham’s Law – with bad common-law decisions driving out what the FDA and the medical profession otherwise view as proper medical practice. Patients who would benefit from tort-contraindicated uses lose those benefits, even where data reviewed by the FDA show benefits exceeding harm. That would be the practical effect of allowing plaintiffs to bring, and common-law juries to decide, failure to contraindicate claims.

Thus, not only are failure to contraindicate claims preempted under the rationales discussed above, but as a matter of public policy, such claims should not be recognized in the first place.