To the extent that Defendants did not know—they should have known of the association via an exercise of pharmacovigilance years before the FDA’s 2008 Alert regarding suicidality with antiepileptic drugs. The liability for any such lack of knowledge by Defendants falls squarely on Defendants’ shoulders for not properly developing and executing safety surveillance activities consistent with 21 C.F.R. § 314.80. Additionally, despite illegally promoting and selling Neurontin for off-label, unapproved uses, Defendants failed to exercise safety surveillance activities in terms of reviewing and considering psychiatric adverse events reported with the very intended “off-label” uses for which Defendants knew Neurontin was being used in the marketplace, and for which Defendants’ Neurontin labeling was admittedly inadequate.74 C. NEURONTIN HAS THE CAPACITY TO CONTRIBUTE TO MOOD AND BEHAVIORAL DISTURBANCES, INCLUDING SUICIDALITY.

¶ 92, see id.¶¶ 45-54, 85-89 (citing 21 C.F.R. §§ 314.80, 314.81); Uloric Compl.

¶ 92, see id.¶¶ 45-54, 85-89 (citing 21 C.F.R. §§ 314.80, 314.81); Uloric Compl.

81…” See Exhibit 7 (sample Form 356h); see also Uloric Complaint at ¶ 23 (discussing NDA requirements and Form 356h); see also Actos Complaint at ¶¶ 45-54 (same). Thus, with each new drug application and supplemental application Takeda submitted to the FDA to obtain permission to market and sell the drugs at issue to patients, including Medicaid and Medicare patients, Takeda certified it would comply with all adverse event reporting requirements, including but not limited to the reporting requirements delineated in 21 C.F.R. § 314.80. See Actos Complaint ¶¶48, 49.

As explained, governing federal regulations expressly state that an AER does not indicate “that the drug caused or contributed to an adverse effect.” 21 C.F.R. § 314.80(k). The FDA has explained that the information in AERs “has not been scientifically or otherwise verified” and “there is no certainty that the suspected drug caused the reaction”; the “event . . . may have occurred by chance at the same time the suspected drug was taken.”

Federal regulations require the NDA holder to “promptly review all adverse drug experience information obtained or otherwise received by the [NDA holder] from any source.” 21 C.F.R. § 314.80(b).

While generic pharmaceutical manufacturers are not authorized independently to update the labels for their products, Mensing, 564 U.S. at 613, they otherwise have similar responsibilities to those of NDAholders: they are also required to monitor the market and to sub- mit annual reports and supplementalapplications (when appropriate) to FDA. See 21 C.F.R. §§ 314.70, 314.71, 314.80, 314.81, 314.97, 314.98; Abbreviated New Drug Application Regulations, 57 Fed. Reg. 17,950, 17,961 (Apr. 28, 1992). B. Since 1996, at least 134 state and federal decisions have concluded that pharmaceutical manufacturers cannot be held liable for products made and sold by others.

. If you issue a letter communicating important information about this drug product (i.e., a “Dear Health Care Professional” letter), we request that you submit a copy of the letter to this NDA and a copy to the following address: MEDWATCH, HFD-410 FDA 5600 Fishers Lane Rockville, MD 20857 We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). If you have any questions, please contact: Mr. Russell Fortney Case 2:16-cv-02362-ER Document 30-4 Filed 10/25/16 Page 2 of 4 NDA 18-972/S-030 Page 2 Regulatory Health Project Manager (301) 594-5311 Sincerely, {See appended electronic signature page} Norman Stockbridge, M.D., Ph.D. Acting Director Division of Cardio-Renal Drug Products Office of Drug Evaluation I Center for Drug Evaluation and Research Enclosure

Although Novartis did not own the NDA for Brethine in 2007, it did ownit until 2001 and wasresponsible for the label information prior to that time. (21 C.F.R. § 314.80(b).) The minorsallege there was sufficient informationprior to 2001 regarding the risk of fetal harm in using terbutaline as a maintenancetocolytic to require Novartis to revise the drug label.

50 or, in the case of a 505(b)(2)application, Case 1:08-cv-00358-JL Document 142 Filed 03/23/10 Page 35 of 59 33 an effective approved application,” who must comply with the provision. 21 C.F.R. §314.80(b). Both §314.