PROMOTIONAL MATERIALS You may request advisory comments on proposed introductory advertising and promotional labeling. To do so, submit, in triplicate, a letter requesting advisory comments, the proposed materials in draft or mock-up form with annotated references, and the package inserts to: Food and Drug Administration Center for Drug Evaluation and Research Division of Drug Marketing, Advertising, and Communications 5901-B Ammendale Road Beltsville, MD 20705-1266 As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the package insert(s), at the time of initial dissemination or publication, accompanied by a Form FDA 2253. For instruction on completing the Form FDA 2253, see page 2 of the Form.

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

Submit both copies together with a copy of the proposed or final printed labeling to the Division of Drug Marketing, Advertising, Case 3:17-cv-02609-WHO Document 41-2 Filed 05/22/17 Page 2 of 3 and Communications (HFD-40). Please do not use Form FD-2253 (Transmittal of Advertisements and Promotional Labeling for Drugs for Human Use) for this initial submission. We call your attention to 21 CFR 314.81(b)(3) which requires that materials for any subsequent advertising or promotional campaign be submitted to our Division of Drug Marketing, Advertising, and Communications (HFD-40) with a completed Form FD-2253 at the time of their initial use. Validation of the regulatory methods has not been completed.

The brand-name manufacturer also must submit annual reports to the FDA onsignificant information,including information that might affect the safety, effectiveness, or labeling of the product. (21 C.F.R. § 314.81.) Likewise, a generic manufactureris required to submit these reports to the FDA. (21 C.F.R. §§ 314.92, 314.98.)

NDA holders must also submit to the FDA annual reports summarizing all information received about their medicines, including adverse drug events andclinicaltrial results. (21 C.F.R. § 314.81(b)(2).) Apart from adverse-event reporting, the FDA frequently requires NDAholders to undertake additional clinical studies after approval.

70 .................................................................................................................... 5, 15 21 C.F.R. § 314.80 ........................................................................................................................ 14 21 C.F.R. § 314.81 ........................................................................................................................ 14 21 C.F.R. § 314.105 ...................................................................................................................... 14 21 C.F.R. § 314.

pdf; FDA, Approval Letter, RECTIV, NDA 21-359 (June 21, 2011) (requiring post-marketing studies for ages 1 month to 16 years), available at http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/021359s000ltr.pdf; see also FDA, Postmarket Requirements and Commitments Database, available at http://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm (searchable database for Case 1:12-cv-00763-ERK-VVP Document 71 Filed 07/20/12 Page 3 of 8 PageID #: 1818 4 post-marketing studies required under PREA). In such cases, drug sponsors are required to submit an annual report to FDA detailing progress towards completing the required post-marketing studies, see 21 U.S.C. § 355c (a)(3)(B)(i)(I); 21 C.F.R. § 314.81, and the product labeling must indicate that the drug has not been found safe and effective for the relevant pediatric age group, see 21 C.F.R. § 201.57(c)(9)(iv)(E)-(F); see also Embeda Label at 11 (Aug. 13, 2009) (“The safety and efficacy of EMBEDA in patients less than 18 years of age have not been established.”)

passim FED.R.EVID., Rule 201 ...................................................................................................................29 21 C.F.R. 314.80 ............................................................................................................................17 21 C.F.R. 314.81 ............................................................................................................................17 21 U.S.C. § 331(e) .........................................................................................................................33 21 U.S.C. § 333(a) .........................................................................................................................33 21 U.S.C. § 355(a) .............................................................................................................17, 21, 34 21 U.S.C. § 355(e) .............................................................................................................18, 21, 35 21 U.S.C. § 355(k) .........................................................................................................................33 31 U.S.C. §§ 3729, et seq....................................................................................................... passim Wall, Fa

In addition to these adverse event reports, companies may also file regular reports of other field experiences and any information that “might affect the safety, effectiveness, or labeling of the drug.” 21 C.F.R. § 314.81. In addition to manufacturer reporting, FDA also maintains its own safety monitoring database: the Sentinel System, “a national, integrated, electronic system for monitoring medical product safety.”