110(b)(3) (noting the opportunity for an administrative hearing under 21 C.F.R. § 314.200 if FDA refuses to approve an ANDA under 21 C.F.R. § 314.127); 314.127(a)(1) (requiring FDA to refuse to approve an ANDA if manufacturing operations are noncompliant); 314.

103 In this case, there have been thousands of accidental exposures to children causing severe adverse events including hospitalization and death. RBP now has evidence showing that when buprenorphine for opioid addiction is packaged in child-resistant unit-dose, versus multi-dose packaging, the risks of pediatric 102 103 21 C.F.R. § 314.127(a)(ll); FDC Act§ SOSG)(4)(I). 21 C.F.R. § 314.161(A)(l). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 44 of 49 Division of Dockets Management September 25, 2012 Page 44 exposure are significantly reduced. In response to these findings, RBP discontinued marketing of Suboxone tablets (NDA 20-733).

127, in turn, provides that FDA will refuse to grant a tentative or final approval for an ANDA for a variety of reasons, including if “[t]he methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug product are inadequate to ensure and preserve its identity, strength, quality, and purity.” 21 C.F.R. § 314.127(a)(1). In the preamble to its proposed rule promulgating the ANDA regulations, FDA observed that “an ANDA . . . may be approved with a delayed effective date, as specified by the agency in its approval letter.”

C. The "Same Labeling" Requirement The statute provides that an "abbreviated application for a new drug shall contain . . . (v) information to show that the labeling proposed for the new drug is the same as the labeling approved for the listed drug . . . except for changes required . . . because the new drug and the listed drug are produced or distributed by different manufacturers." 21 U.S.C. §§ 355(j)(2)(A)(v), 355(j)(4)(G); 21 C.F.R. §§ 314.127(a)(7), 314.94(a)(8)(iv).11 The labeling for an innovator drug generally includes, among other things, information on clinical and preclinical studies conducted on the innovator product.

The FDA approves a section viii request only if the labeling omission does not “render the proposed [generic] drug product less safe or effective than the [pioneer] drug.” 21 C.F.R. § 314.127(a)(7). A section viii statement is improper also if the proposed labeling includes any part of the patent- protected uses described in the Orange Book: “[I]f the generic’s proposed carve-out label overlaps at all with the brand’s use code,” then a section viii statement is improper, and the generic company must use a paragraph IV certification.

Among other information, an ANDA must include data showing that the generic drug product is bioequivalent to the innovator product. 21 U.S.C. § 355(j)(2)(A)(iv), (j)(4)(F); 21 C.F.R. §§ 314.127(a)(6)(i), 314.94(a)(7). After approval, FDA may reassess a drug’s safety and consider whether changes in the information available justify and meet the statutory criteria for taking regulatory action.

. 264 21 U.S.C. § 355(j)(5)(B)(iv)(II)(dd)(AA); 21 CFR § 314.127(a)(7) (“FDA will refuse to approve” an ANDA if “[i]nformation submitted in the [ANDA] is insufficient to show that the labeling proposed for the drug is the same as the labeling approved for the [RLD] except for changes required because of differences approved in a petition under § 314.93 or because the drug product and the [RLD] are produced or distributed by different manufacturers or because aspects of the listed drug's labeling are protected by patent, or by exclusivity, and such differences do not render the proposed drug product less safe or effective than the listed drug for all remaining, nonprotected conditions of use.”

Among these conditions, FDA cannot approve an application for a generic drug if it finds that “the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug are inadequate to assure and preserve its identity, strength, quality, and purity.” 21 U.S.C. §355(j)(4)(A); see also 21 C.F.R. § 314.127(a) (“FDA will refuse to approve an [ANDA if] . . . [t]he methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug product are inadequate to ensure and preserve its identity, strength, quality, and purity.”).

Under the Hatch-Waxman Amendments, in order to obtain FDA approval, an ANDA must include information showing that the generic drug product is bioequivalent to the pioneer drug product. 21 U.S.C. § 355(j)(2)(A)(iv), (j)(4)(F); 21 C.F.R. §§ 314.127(a)(6)(i), 314.94(a)(7).

See also the FDA implementing regulations at 21 C.F.R. § 314.94(a)(8)(iv)(applicant must submit side-by-side comparison of proposed labeling with labeling of the reference listed drug, with all differences annotated and explained; no differences permitted, except as enumerated therein) and 21 C.F.R. §314.127(a)(7)(FDA will refuse to approve an ANDA if applicant cannot demonstrate that the labeling proposed for the drug is identical to that of the ref ence listed drug, but for the Case 1:04-cv-10981-PBS Document 673 Filed 03/12/2007 Page 10 of 23 11 enumerated exceptions). Moreover, the generic label must also be maintained in conformity with that of the reference listed drug thereafter, on pain of withdrawal of approval of the ANDA.