See Kordel, 335 U.S. at 350. In addition, 21 C.F.R. § 202.1(e)(4)(i)(a) provides that statements of effectiveness in advertisements “shall not recommend or suggest” unapproved uses, but it does not proscribe any speech outside that specific context. FDA does not rely on either of these regulations to support its authority over manufacturer communications related to unapproved uses of approved prescription drugs, see London Decl.

21 U.S.C. § 352(n). FDA, however, has proscribed any “advertisements” that “recommend or suggest any use that is not in the labeling accepted in [the drug’s] approved new-drug application,” 21 C.F.R. § 202.1(e)(4)(i)(a), effectively prohibiting any direct-to- physician advertisements suggesting off-label uses. Third, FDA regulations concerning the FDCA’s misbranding provisions also restrain manufacturer speech.

80. 8 “Labeling,” defined by 21 U.S.C. §321(m) and 21 C.F.R. § 202.1, includes not just the prescribing information, but also any written, textual, or graphic material “accompanying” the medication, such as advertisements in medical journals. See Kordel v. United States, 335 U.S. 345, 350 (1948).

In our opening briefs, we showed that the California Supreme Court and the California court of appeals have adopted the C ntral Hudson test as the standard for evaluating compelled commercial subsidies and compelled commercial speech. Gerawan Farming, Inc. v. Kawamura, 33 30 See, e.g., 15 U.S.C. § 78l (registration requirements for securities, including anti-fraud disclosures); 21 C.F.R. § 202.1 (regulating drug advertisements to protect consumers fro confusing or misleading advertisements); 15 U.S.C. §§ 68-68j (requiring labeling of wool products’ actual content, to “protect consumers against the concealment of substitutes for wool in products claimed to be made wholly or partially of wool” (Marcus v. FTC, 354 F.2d 85, 87 (2d Cir. 1965)); 15 U.S.C. §§ 1667-1667f (protecting consumers against inadequate and misleading leasing information); Cal. Civ. Code § 1916.

See 7/17/06 P.R. Many drugs receive FDA approval, and are successfully marketed, despite risk of liver-related side effects, as anyone who has seen television advertisements for prescription drugs knows. See 21 C.F.R. § 202.1(e)(1) (requiring disclosure of side effects in drug advertising). Case 4:07-cv-04972-CW Document 36 Filed 06/02/2008 Page 18 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 REPLY IN SUPPORT OF DEFENDANTS’ MOTION TO DISMISS CASE NO. 4:07-CV-04972-CW 13 reveal supposed “problems that had already arisen” in Threshold’s ongoing Phase 2 and 3 clinical trials.

The FDCA and the FDA’s regulations define “labeling” to include all hard-copy promotional material “upon” or “accompanying” the drug, which includes the package insert for the drug, and everything from booklets to calendars, if the material is textually related to the drug. 21 U.S.C. § 321(m); 21 C.F.R. § 202.1(1)(2). FDA’s regulation of prescription drug labeling would be meaningless if [the manufacturer] were free to undermine and contradict FDA-mandated warnings through other publication means.

Thus, Mylan’s failure to send letters to physicians indicating that paroxetine’s adult suicidal behavior risk was higher than the class-wide risk contained in the label (clinical trials of paroxetine specifically showed an approximate seven times greater risk of adult patients of all ages experiencing suicidal behavior) would not be preempted by the FDCA since compliance with state and federal law is possible. As the Court in Lyman v. Pfizer, Inc. explains: Case: 1:12-cv-06403 Document #: 100 Filed: 07/24/13 Page 14 of 16 PageID #:1518 15 Although the Mensing Court concluded that generic drug manufacturers were precluded from issuing substantial additional warnings that were inconsistent with or contrary to the drug’s approved labeling, it did not rule that generic drug manufacturers were precluded from issuing “labeling,” as that term is defined in 21 U.S.C. § 321(m) and 21 C.F.R. § 202.1(l)(2), that is “consistent with and not contrary to ... approved or permitted labeling.” 21 C.F.R. § 201.

Id. at 2576 (if generic drug manufacturers were to provide warning information directly to doctors that the brand manufacturer did not communicate to doctors in identical fashion, it “would inaccurately imply a therapeutic difference between the brand and generic drugs”); see also 21 C.F.R. § 202.1(l)(2) (expansively defining drug labeling to include, inter alia, brochures, mailings, letters, and literature). For these reasons, dozens of federal courts Case: 2:10-cv-00142-JLG-EPD Doc #: 67 Filed: 10/19/12 Page: 14 of 17 PAGEID #: 549 15 have found that allegations of fraud, misrepresentation, and concealment ultimately depend upon an alleged failure to adequately warn about a drug’s risks, and thus are all preempted.

Because it requires disclosure of purely factual information, Ordinance 40-08 is no different than numerous other commercial disclosure requirements mandated by federal and state law, including the NLEA's nutrition facts panel. See, e.g., 21 U.S.C. § 343(q)(1) (nutritional labeling); 15 U.S.C. § 78 l (securities disclosures); 15 U.S.C. § 1333 (tobacco labeling); 21 C.F.R. § 202.1 (disclosures in prescription drug advertisements). Because Ordinance 40-08 requires the posting of "'purely factual and uncontroversial' commercial information," the "reasonableness" standard set forth in Zauderer is the proper framework to apply in determining whether Ordinance 40-08 violates the First Amendment.

Innumerable federal and state regulatory programs require the disclosure of product and other commercial information. See, e.g., 2 U.S.C. § 434 (reporting of federal election campaign contributions); 15 U.S.C. § 78l (securities disclosures); 15 U.S.C. § 1333 (tobacco labeling); 21 U.S.C. § 343(q)(1) (nutritional labeling); 33 U.S.C. § 1318 (reporting of pollutant concentrations in discharges to water); 42 U.S.C. § 11023 (reporting of releases of toxic substances); 21 C.F.R. § 202.1 (disclosures in prescription drug advertisements); 29 C.F.R. § 1910.1200 (posting notification of workplace hazards); Cal.