In its new decision, the court first noted that under 21 C.F.R. §201.80, a manufacturer must revise labeling "to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug; a causal relationship need not have been proved." Under 21 C.F.R. §314.70(c), a manufacturer may unilaterally add or strengthen a contraindication, warning, precaution or adverse reaction upon submission of a "changes being effected" [CBE] supplement. The court now thinks that the FDA's power to disapprove a label "does not make the manufacturer's voluntarily strengthened label a violation of federal law, which is what it would take to establish an actual conflict between state tort law and federal law.”

[8] 21 U.S.C. §332 (injunctive relief); 21 U.S.C. §333 (civil and criminal penalties); 21 U.S.C. §334 (seizure).[9] 21 C.F.R. §314.70(c)(6)(iii)(A)-(C).[10] Levine, 183 Vt. at 91.

[11] For most substantive changes to product labeling, a drug application holder is required to seek and obtain FDA approval for the change. See 21 C.F.R. § 314.70(b). The CBE regulation, however, permits certain labeling changes to be made effective upon the FDA’s receipt of a supplement containing the new information, including (A) [t]o add or strengthen a contraindication, warning, precaution, or adverse reaction. . . (B) [t]o add or strengthen a statement about drug abuse, dependence, psychological effect, or overdosage; (C) [t]o add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the drug product; (D) [t]o delete false, misleading, or unsupported indications for use or claims for effectiveness; or (E) [a]ny labeling change normally requiring a supplement submission and approval prior to distribution of the drug product that FDA specifically requests be submitted under this provision.

So the question devolves to whether an FDA tentative monograph for an OTC drug is something that, like Wyeth v. Levine, 555 U.S. 555 (2009), can be amended at will, or is it something, like the Mensing/Bartlett line of cases, that is cannot be deviated from without prior FDA approval. The “changes being effected” regulation that the Levine court found dispositive, 21 C.F.R. §314.70, is explicitly limited to “changes to an approved NDA.” Since NDAs are not required for OTC drugs subject to the monograph system, that would appear to be out.

FDA regulations provide that once a drug, whether generic or brand-name, is approved, the manufacturer is prohibited from making any major changes to the qualitative or quantitative formulation of the drug product, including inactive ingredients, or in the specifications provided in the approved application. 21 C.F.R. § 314.70(b)(2)(i). Moderate changes must be reported to the FDA at least 30 days prior to distribution of the drug product made using the change.

In contrast, the Supreme Court in Levine held that identical claims against a name-brand manufacturer were not preempted. Under the FDA’s Changes Being Effected (CBE) regulation, 21 C.F.R. § 314.70(c)(6)(iii), name-brand manufacturers under certain circumstances are permitted to independently modify the language of an FDA-approved label. Thus, where the CBE procedure is available, a state law penalizing name-brand manufacturers for not exercising their ability to modify their warning labels is not preempted.

We’re not going to get into most of them from the Court‘s 48-page decision (we’ll leave that to the folks over at the Drug & Device Law Blog for whom preemption is manna), but we do think the Circuit Court’s decision on RLD status and failure-to-warn liability is important to our readers (pages 18-20 of the decision).Pointing to and quoting from a July 2013 FDA guidance document, titled Safety LabelingChanges–Implementation of Section 505(o)(4) of the FD&C Act, the Court says that RLD designation of an ANDA’d drug product does not equate to NDA status. That FDA guidance states, in relevant part, that while RLD designation generally means that the application sponsor must submit labeling changes when it becomes aware of new safety information, that obligation does not apply to ANDA sponsors:Under existing FDA regulations, ANDA holders cannot make labeling changes through the formal supplement process under 21 CFR 314.70 in all circumstances in which NDA holders can because an ANDA’s labeling must be the same as the NDA RLD’s labeling. Accordingly the changes-being-effected supplement process under 21 CFR 314.70(c) is not expressly available to ANDA holders except to match the RLD labeling or to respond to FDA’s specific request to submit a labeling change under this provision.

That guidance, titled "Safety Labeling Changes — Implementation of Section 505(o)(4) of the FD&C Act," was released in final form earlier this week (see here). Among other things, both the draft and final guidance clarify that:Under existing FDA regulations, ANDA holders cannot make labeling changes through the formal supplement process under 21 CFR 314.70 in all circumstances in which NDA holders can because an ANDA’s labeling must be the same as the NDA RLD’s labeling (with some exceptions, as described in 21 CFR 314.94(a)(8)(iv)). Accordingly, the changes-being-effected supplement process under 21 CFR 314.70(c) is not expressly available to ANDA holders except to match the RLD labeling or to respond to FDA’s specific request to submit a labeling change under this provision.

(Public Citizen submitted an amicus brief in the Mensing case in support of Respondents.)The Public Citizen petition makes three requests:(1) That FDA amend, through notice and comment rulemaking, its PAS and CBE regulations at 21 C.F.R. § 314.70(a) to specify that subsections (b) and (c) apply to ANDA sponsors. Such an amendment, says Public Citizen “might also make exceptions to reflect situations in which the agency believes that particular ANDA holders lack an adequate basis to make labeling changes, such as, perhaps, during the first few months after the first ANDA holder enters the market or for an ANDA holder that sells very few prescriptions of a drug (for example, under 1,000 prescriptions per year);”(2)That FDA amend its regulation at 21 C.F.R. § 314.150(b)(10) (permtting ANDA approval to be withdrawn if a generic drug’s approved labeling differs from that of the RLD) “to specify that this regulation does not apply to ANDA holders permitted to supplement labeling through CBE or PAS procedures;” and(3)That FDA clarify in its regulations (and specifically 21 C.F.R. § 201.57(c)(6)(i)(A)) “that all ANDA holders are required to report safety concerns to the FDA as soon as they become aware of a clinically significant hazard.

g that the FDA’s approval of a drug’s labeling reflects the agency’s definitive judgment regarding risks that must be shielded from the possible second-guessing that might take place in a failure-to-warn case. . . .But in our view, the FDA is wrong to focus on the moment of approval as determinative of the preemption question. The relevant timeframe is postapproval, and the question, in our opinion, is what did the FDA and the drug company know about a drug’s risks at the time the patient-plaintiff sustained the injury.The authors also argue that a “Rule of Construction” included in the recently-enacted FDA Amendments Act (“FDAAA”) undercuts FDA’s pro-preemption position.In this provision, which was added to FDC Act § 505(o) by FDAAA § 901(a), Congress amended the law to state that the Agency’s labeling authority over drugs and biologics “shall not be construed to affect the responsibility of the [manufacturer] to maintain its label in accordance with existing requirements, including [21 C.F.R. § 314.70 and § 601.12] (or any successor regulations).”This provision was reportedly included in FDAAA instead of an express preemption provision.