70(c)(2)(i) FDA approval is not required for certain labeling changes related to pharmaceuticals. Specifically, 21 C.F.R. § 314.70(c)(2)(i) allows for changes in labeling to be made prior to FDA approval under circumstances to “add or strengthen a contraindication, warning, precaution, or adverse reaction”. In this litigation, despite clinical trial psychobiologic adverse events and postmarketing safety surveillance data available to Defendants that demonstrated an association of Neurontin 64 “The purpose of the Gabapentin Data Capture Aid is to systematically collect and assemble all available information . . .involving adverse events of special interest.”

Rather, Judge Breyer accepted FDA’s rationale in the Final Rule on Labeling that it is the final arbiter of label content, even when the “Changes Being Effected Amendment” provisin is utilized. Teva agrees and urges this Court t follow In re Bextra, but notes that the Court need not go that far to conclude that the claims against Teva are preempted, based upon Teva’s inability under any circumstances to utilize 21 C.F.R. § 314.70(c) to vary its label from that prescribed to it by FDA. Case 1:04-cv-10981-PBS Document 673 Filed 03/12/2007 Page 18 of 23 19 II.

57(c) of this chapter.” 21 C.F.R. § 314.70(c)(6)(iii)(A) (2006) (emphasis added). Biogen is the holder of the approved application for Tysabri in the United States and is responsible by law and by its agreement with Elan for pharmacovigilance activities in the United States and Elan acts as the distributor.

In turn, any change to the FPI section that necessitates a corresponding change to Highlights, also cannot be changed independently. Finally, Highlights must contain a list of substantive changes to the Indications and Usage and the Warnings and Precautions sections of the FPI approved by FDA or authorized under 21 C.F.R. §314.70. The list must in- clude “each section’s identifying number and the date (month/year) on which the change was incorporated in labeling.”

These changes were of the type Case 1:16-cv-02372-ABJ Document 13 Filed 05/08/17 Page 23 of 36 17 that required Ipsen to obtain approval from FDA before marketing the drug. 21 C.F.R. § 314.70(b)(2)(i), (v)(A), (vi); A.R. 40 (approving Ipsen’s “‘Prior Approval’ supplemental new drug application”). In short, the FDCA and FDA regulations are clear that these changes rendered Somatuline ED a new drug that, as such, required new FDA approval.

Second, the CBE Regulation only permits manufacturers to “delete false, misleading, or unsupported indications for use or claims for effectiveness.” 21 C.F.R. § 314.70(c)(6)(iii)(D). Plaintiffs inaccurately describe the Regulation as permitting manufacturers to “correct” such information, as opposed to being limited to deletion of the information.

Pursuant to the CBE Regulation, a manufacturer may “add or strengthen” warnings or instructions related to the safety, dosage or administration of the drug in light of new information received by the manufacturer. See 21 C.F.R. § 314.70(c)(6)(iii)(A)–(C). A manufacturer may also “delete false, misleading, or unsupported indications for use or claims for effectiveness” based on newly acquired information.

C. A GENERIC MANUFACTURE CAN EMPLOY OTHER MEANS TO WARN OF ITS PRODUCT’S RISKS Even if this Court were to conclude that Actavis could not have invoked the CBE process to strengthen their metoclopramide warnings, preemption would still not be appropriate because Actavis had other means to warn of their products’ risks. First, there is no dispute that generic drug manufacturers could have sought to strengthen their warnings about the risks of tardive dyskinesia caused by prolonged exposure to metoclopramide through the prior approval supplement process, 21 C.F.R. § 314.70(b), but chose not to do so. In turn, even before FDA approval for a labeling change was obtained, Actavis was free to employ other means to warn health care professionals and consumers of the increased risk of tardive dyskinsia from prolonged exposure to metoclopramide.

The “major changes” regulation addressed by the Court in Bartlett specifies that even a change to a medicine’s inactive ingredients constitutes a major change that requires FDA approval. See 21 C.F.R. § 314.70(b)(2)(i); Yates, 808 F.3d at 296, 298–99. The Bartlett Court also confirmed that “increasing the ‘usefulness’ of a product or reducing its ‘risk of danger’ would require redesigning the drug: A drug’s usefulness and its risk of danger are both direct results of its chemical design and, most saliently, its active ingredients.”

If an applicant seeks a “major” change in the approval, FDA must approve an ANDA supplement before drugs affected by the change can be distributed. 21 C.F.R. § 314.70(b). If an applicant seeks a “moderate” change in the approval, the applicant must submit an ANDA supplement to FDA at least 30 days before distributing drugs affected by the change.