57(e), an epidemiological association or a causal association is NOT required for there to be an obligation to warn of a risk of a serious health hazard. See 21 C.F.R. § 201.57(e); the standard is “reasonable evidence”. In fact, the FDA contemplates black box warnings in the absence of any clinical data which implies epidemiological evidence is not always needed.

Repeatedly, Lilly calls the label that accompanies the drug a “physician package insert” (MTD at 1, 2, 22), even though the prescribing doctor does not fill the Cymbalta prescription. Compare with 21 C.F.R § 201.57 (referring to “labeling” of prescription drugs). Treating doctors are not “consumers” under the applicable consumer protection acts.

Mr. McDowell’s central claim in this lawsuit is that Lilly misled medical professionals about the rate of discontinuation symptoms by listing the events seen in the clinical trials “at a rate greater than or equal to 1%,” consistent with the Federal Regulations. See 21 C.F.R. § 201.57(c)(7)(ii)(A). To be clear, Lilly submits that this theory is legally deficient to establish liability and that there is nothing improper about failing to list specific rates for individual discontinuation adverse reactions.

# 116 at 3/43 quoting HUMIRA label. Again, under the express wording of 21 CFR §201.57, as amended in 2006, Abbott could not put this language into the precautions section of its Humira label unless it believed that there is reasonable scientific evidence of a “causal association.” Indeed, one of the principal cases cited by Abbott specifically makes the point that “lymphoma caused by -8- Case 4:11-cv-00105 Document 153 Filed in TXSD on 07/30/13 Page 13 of 31 immunosuppressant drugs is well-understood” in medicine.

Even if FDA regulations did establish only a minimum safety standard that a manufacturer could exceed by including additional warnings – as plaintiffs no doubt will argue – Pfizer was not free to file a CBE supplement regarding an increased risk of suicide-related events because there was no “reasonable evidence” of an association supporting such an addition to the labeling. See 21 C.F.R. § 201.57(c)(6)(i). See O’Neal, 2008 WL 275782, at *13 (“Absent reasonable evidence of a risk, GSK had no basis to petition FDA and simply did not have the option under federal law to include or secure a warning for [a] risk [of suicide] in the drug’s labeling.

99 to Marino Cert. - Expert Report of Dr. Joseph Berger (“Berger Report”) at p. 6; see also 21 C.F.R. § 201.57(c)(1); 44 Fed. Reg. 37434, 37448 (FDA June 26, 1979) (“To ensure the significance of boxed warnings in drug labeling, they are permitted in labeling only when specifically required by FDA.”)

Contrast this with the “warnings and precautions” section of the label which: [M]ust describe clinically significant adverse reactions (including any that are potentially fatal, are serious even if infrequent, or can be prevented or mitigated through appropriate use of the drug), other potential safety hazards (including those that are expected for the pharmacological class or those resulting from drug/drug interactions), limitations in use imposed by them (e.g., avoiding certain concomitant therapy), and steps that should be taken if they occur (e.g., dosage modification). (21 C.F.R. § 201.57(c)(6)). While everything in the warnings and precautions section also qualifies as an adverse event, the converse is not true.

Generally, separate investigations are necessary to support an indication for that population, as distinct from an indication for an adult population. See generally, FDCA $ 505A, 21 U.S.C. § 355a; 21 C.F.R. § 201.57(f}(ii) (2005). Thus, for example, if a drug is indicated only for an adult population, but is promoted by its manufacturer for a pediatric population, the manufacturer would be subject to a charge under section 301(d) as well as to a charge under section 502(f)(1), The availability of a new-drug charge in this type of situation demonstrates conclusively that a drug intended for one patient population is a different new drug from the otherwise identical drug intended for a different patient population.

44 Fed. Reg. 37,434, 37,436 (June 26, 1979); 21 C.F.R. § 201.57; 21 C.F.R. § 201.80.

The labeling sections are to be listed in the order in which they appear in the FPI and must be listed in Highlights for at least 1 year after the date of the labeling change. 21 C.F.R. §201.57(a)(5). Again, all changes to Highlights require pre-approval.