Opinion ID: 70441
Heading Depth: 2
Heading Rank: 1

Heading: The Changes Being Effected Process

Text: Where, as here, the requisite labeling change would add or strengthen a contraindication, warning, precaution, or adverse reaction, [74] to reflect information not previously submitted to the [FDA] and is based on sufficient evidence of a causal association, it qualifies for the CBE process, [75] meaning the manufacturer may make the labeling change upon filing its supplemental application with the FDA; it need not wait for FDA approval. [76] The district court focused much of its analysis on the availability of the CBE process to generic manufacturers. Just as nothing in the text of the Hatch-Waxman Amendments forbids a generic manufacturer from changing its drug's label from the listed version's post-approval, [77] the CBE regulation also does not, on its face, distinguish between generic and name brand drug manufacturers; that is, it does not forbid a generic manufacturer from using the CBE process to unilaterally change a label. Located at 21 C.F.R. § 314.70, the regulation provides that the holder of an approved applicationnot just an approved new drug applicationmay commence distribution of the drug product involved upon receipt by the agency of a supplement for the change. [78] Unsupported by the regulation's text, then, Actavis must seek support from FDA commentary for its argument that generic manufacturers cannot use the CBE process. Specifically, when the Agency revised the CBE regulation following the Hatch-Waxman Amendments, it reminded ANDA applicants that, as noted in paragraph 4 above, the labeling for an ANDA product must, with few exceptions, correspond to that for the reference listed drug. [79] At first glance, this provision seems to provide arguable support for Actavis's view: the comment, unlike others it cites, refers to the labeling for an ANDA product,  rather than the labeling proposed for a product in an ANDA application  and thus could be read to mandate that a generic's labeling remain the same as the listed drug's after approval. A closer examinationone that accounts for the comment's reference to paragraph 4 indicates, however, that the FDA's explanation was still fixed on the pre-approval label. Paragraph 4 turns down a suggestion that the FDA accept ANDA's with warnings or precautions in addition to those on the reference listed drug's label, by noting that the applicant's proposed labeling [must] be the same as that of the listed reference drug with exceptions not relevant here. [80] So, once again we encounter an admonition that the content of a generic drug's labeling during the ANDA approval process conform to that of the corresponding listed drug; there is no direction, however, as to what may happen afterwards. It would be a stretch then, in light of paragraph 4's cameo in the FDA's comment to the CBE regulation, to read it as Actavis would have us do, and expand the directive that the labeling proposed for the drug [be] the same as the labeling approved for the listed drug, into the post-approval period, an undemanded play with displacement of traditional state regulation. [81] In addition, these comments accompanied the only change that the FDA made to the CBE regulations when implementing the Hatch-Waxman Amendments: the addition of a paragraph requiring applicants to comply with the patent information requirements under [21 U.S.C. § 355(c)(2)]. [82] Actavis's preferred reading of these comments is not plausible unless we accept the proposition that the FDA would, in a minor and unrelated revision, express the novel view that generic manufacturers are altogether forbidden from using the CBE process. On the other hand, what the FDA clearly did do to implement Hatch-Waxman cuts against Actavis's position, or at the very least muddies congressional and agency intent: it promulgated 21 C.F.R. § 314.97, entitled Supplements and other changes to an approved abbreviated application. [83] This rule provides that ANDA applicants shall comply with the requirements of §§ 314.70 and 314.71 regarding the submission of supplemental applications and other changes to an approved abbreviated application. [84] The requirements of § 314.70 include, of course, the CBE process. Had the FDA intended to deny generic manufacturers access to the CBE procedures, notwithstanding § 314.97's plain language, we might expect the FDA to say so, either in § 314.97 or in the CBE provision itself. If this was the FDA's intent and the industry's understanding at the timeit passed over the opportunity to make that clear in these provisions promulgated in Hatch-Waxman's wake. As the regulations stand, however, we cannot tack the words only when a listed drug manufacturer has first revised its label onto the end of § 314.97as Actavis's argument begs. Nonetheless, Actavis insists that the CBE process is only available to generic manufacturers to implement changes already made to the name brand's label: in other words, that § 314.97 only requires that generics follow name brand labeling if and when a change is made by the name brand manufacturer. For that reason, Actavis says, the FDA rejected a comment suggesting that ANDA holders be required to submit drug labeling at periodic intervals to ensure that the generic label matched its listed counterpart. The FDA found such a procedure unnecessary because existing reporting requirements at 21 C.F.R. § 314.70 [including the CBE provision] ensure that labeling changes are brought to FDA's attention in an appropriate and timely fashion. [85] The FDA will then advise ANDA holders of changes to be made after approval, but postapproval changes resulting from the expiration of exclusivity or patent protection are the responsibility of the ANDA holder. [86] While this comment surely indicates that a generic drug manufacturer should use the CBE process to enact changes endorsed by the FDA, it does not say, however, that the process was not also intended to allow ANDA holders to act independently from the name brand manufacturers. Actavis also directs us to the FDA's rejection of yet another comment as part of administrative implementation of Hatch-Waxman. This time, it is one that suggested empowering ANDA applicants to deviate from the labeling for the reference listed drug to add contraindications, warnings, precautions, adverse reactions, and other safety-related information. [87] In response, the FDA reiterated that the ANDA product's labeling must be the same as the listed drug's product labeling because the listed drug product is the basis for ANDA approval. [88] Because [c]onsistent labeling will assure physicians, health professionals, and consumers that a generic drug is as safe and effective as its brand-name counterpart, the FDA instructed an ANDA applicant [who] believes new safety information should be added to a product's labeling ... [to] contact FDA, and FDA will determine whether the labeling for the generic and listed drugs should be revised. [89] Nothing in this response deviates from the now-familiar distinction between the near-unqualified ban on labeling differences pre-approval and their availability after approval of an ANDA. During that latter period, if an ANDA holder believes that new safety information should be added, it should provide adequate supporting information to FDA, and FDA will determine whether the labeling for the generic and listed drugs should be revised. [90] Actavis maintains that this passage demonstrates that, for generic drugs, the FDA decides whether a revision is necessary, not the drug manufacturer. We agree, but the FDA is the ultimate arbiter for all changeswhether prompted by a pioneer manufacturer or a generic one. Every submitted change requires FDA approval, even one that takes effect immediately through the CBE process. The FDA makes these approval decisions based on a comprehensive scientific evaluation of the product's risks and benefits under the conditions of use prescribed, recommended, or suggested in the labeling. [91] Through this review, the FDA is in effect and in fact determin[ing] whether the labeling for the generic and listed drugs should be revised. This is no less true when the FDA reviews the change only after it has been made, as is the case with CBE changes. At best, then, this language is reason for pause, not for a conclusive reading, or a finding of impossibility preemption. Lastly, Actavis emphasizes the FDA's recent statements suggesting that generics cannot use the CBE process and that federal law preempts state-law failure-to-warn claims brought against generics. Actavis first points to two amici briefs filed by the FDA in Colacicco v. Apotex Corp., a case heard in the Eastern District of Pennsylvania [92] and then in the Third Circuit. [93] The briefs argued that Hatch-Waxman and implementing FDA regulations preempt state failure-to-warn claims as to both listed and generic drug manufacturers. [94] In so doing, the FDA took the position that generic manufacturers could not utilize the CBE process at all. [95] The Third Circuit found the plaintiffs' failure-to-warn claims preempted. [96] The Supreme Court later decided Levine, and in light of that holding, granted certiorari in Colacicco, vacated the judgment of the Third Circuit, and remanded for further consideration. [97] In response to Levine, the United States withdrew as amicus in Colacicco and notified the Third Circuit that the United States does not take a position on whether [the state-law failure-to-warn claims] are preempted and has not yet conducted an examination of various preemption issues following the Supreme Court's decision in Wyeth [ Levine ] that would be necessary to inform a position of the United States in this case. [98] Now withdrawn, the FDA's amicus views are muted and we do not consider them. Similarly, Actavis has recently lost another pillar of support. In its briefs, Actavis relies on a footnote in the FDA's proposed 2008 revision to the CBE regulations, which states that CBE changes are not available for generic drugs approved under an ANDA under 21 U.S.C. 355(j). To the contrary, a generic drug manufacturer is required to conform to the approved labeling for the listed drug. [99] But the final version of the rule omits this footnote's language. In fact, the final rulewhich seeks to affirm that a CBE supplement is appropriate ... only to reflect newly acquired information ... and [when] there is sufficient evidence of a causal association with the drugis virtually silent as to generics altogether. The final rule does, however, specifically note that the FDA is amending its regulations regarding changes to an approved [name brand] application. [100] Noting this statement, Actavis points out that the rule does not mention that the changes affect generic applications as well. It then posits that this omission is a sign that the CBE process simply does not apply to generics. We might agree absent three salient insights. First, in its commentary to the final version of the regulation, the FDA removed the footnote that explicitly stated what Actavis asks this court to now hold: that the CBE process does not apply to generics. Second, these regulations were promulgated prior to the Supreme Court's decision in Levine and since that time, the FDA has withdrawn its amicus in Colacicco, as part of an apparent reconsideration of its preemption position. Lastly, the 2008 final rule mentions generics only oncein a citation after a sentence that reads: The agency has clarified by regulation and guidance the types of supplements that should be filed to satisfy a sponsor's obligations to change a drug's labeling .... In support of this statement, the FDA cites 21 C.F.R. § 314.70 (which contains the CBE regulation) and a document entitled Guidance for Industry: Changes to an Approved NDA or ANDA, produced in November 1999. The guidance document notes that [a]ll labeling changes for ANDA products must be consistent with [21 U.S.C. § 355(j)], but otherwise does not distinguish between label changes made by pioneer manufacturers and their generic counterparts. [101] Without explicit reference to the use of the CBE process by generic manufacturers, we decline to read in a bar to its use. The FDA's earlier position, either as amicus or commentator, is instead deprived of all claim to deference, by the fact that it is no longer the agency's position. [102]