For questions about a proposed 505(b)(2) product, the applicant is directed to contact the appropriate Office of New Drugs review division. --- 1 See section 505(j)(2)(A) and 505(j)(4) of the Federal Food, Drug and Cosmetics Act and 21 CFR 314.94 and 314.127.

Unfortunately, history shows that FDA is unlikely to grant the petitioner’s request: that FDA refrain from enforcing its “exception excipient” regulations to permit a “non-exception excipient” change from the RLD.By way of background, FDA’s regulations implementing FDC Act § 505(j)(4)(H), which concerns ANDA approval and inactive ingredient composition and safety, provide that, for certain types of drug products, generic drug formulations may deviate from the RLD formulation only in certain respects. For example, FDA’s regulations for parenteral drug products at 21 C.F.R. § 314.94(a)(9)(iii) state:Generally, a drug product intended for parenteral use shall contain the same inactive ingredients and in the same concentration as the [RLD] identified by the applicant under paragraph (a)(3) of this section. However, an applicant may seek approval of a drug product that differs from the [RLD] in preservative, buffer, or antioxidant provided that the applicant identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product.

21 C.F.R. § 314.60 Patent certification requirements (§ 314.60(f))Requires that if an amendment the 505(b)(2) application does not contain a patent certification or statement, the applicant must verify that the proposed change described in the amendment is not: (1) A new indication or other condition of use; (2) a new strength. (3) an other-than-minor change in product formulation; or (4) a change to the physical form or crystalline structure of the active ingredient (see section VF.1).21 C.F.R. § 314.70Patent certification requirements (§ 314.70(i))Omits proposed § 314 70(i) on patent certification requirements for 505(b)(2) supplements, which is not being finalized at this time (see section V.F.2).21 C.F.R. § 314.90 Waivers (§ 314.90)No substantive changes from the proposed rule (see section V.L.).21 C.F.R. § 314.93 Petition to request a change from a listed drug (§ 314.93)No substantive changes from the proposed rule (see section V.I).21 C.F.R. § 314.94 Method-of-use patent (§ 314.94(a)(12)(iii)(A))Clarifies that an ANDA applicant may submit a statement under section 505(j)(2)(A)(viii) of the FD&C Act if the applicant is not seeking approval for “an” indication or other condition of use claimed by a method-of-use patent rather than “any” indications or other conditions of use claimed by the method-of-use patent (see section V.C.1).Untimely filing of patent information (§ 314.94(a)(12)(vi))Provides that an amendment to the description of the approved method(s) of use claimed by the patent will not be considered untimely filing of patent information if the amendment is submitted within 30 days of a decision by the USPTO or a Federal court that is specific to the patent and alters the construction of a method-of-use claim(s) o f the patent, and the amendment contains a copy of the decision (see section V.B.2.b).After request to remove a patent or patent information from the list (§ 314.94(a)(12)(viii)(B)).Omits the proposed requirement

FDC Act § 505(j)(4)(H) states that FDA must approve an ANDA unless, among other things:information submitted in the application or any other information available to [FDA] shows that (i) the inactive ingredients of the drug are unsafe for use under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug, or (ii) the composition of the drug is unsafe under such conditions because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included.FDA’s regulations implementing FDC Act § 505(j)(4)(H), generally, are found in the Agency’s ANDA content and format regulations at 21 C.F.R. 314.94. Pertinent regulations on inactive ingredient changes for certain types of generic drug products are set forth in 21 C.F.R. § 314.94(a)(9).

FDA added a note to the Orange Book stating: “Applications referencing NDA 021992 Pristiq (Desvenlafaxine Succinate) and challenging the listed patent may be received by the Agency beginning on Feb 29, 2012, four years from the NDA approval date” (see our previous post here).Q26: FDA’s regulation at 21 C.F.R. § 314.94(a)(12)(viii) states, in relevant part, “an applicant who has submitted a paragraph IV patent certification may not change it to a paragraph III certification if a patent infringement suit has been filed against another paragraph IV applicant unless the agency has determined that no applicant is entitled to 180-day exclusivity or the patent expires before the lawsuit is resolved or expires after the suit is resolved but before the end of the 180-day exclusivity period.” What is the status of this regulation?

(IV) Failure to obtain tentative approval. The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.With respect to FDC Act § 505(j)(5)(D)(i)(III), Sandoz argues that as a result of FDA’s regulation at 21 C.F.R. § 314.94(a)(12)(viii), which requires ANDA sponsors to maintain accurate patent certifications and to amend a certification if it is no longer accurate, and Cobrek’s “new” certifications to the ‘116 patent and the ‘083 patent (insofar as the ‘083 patent is relevant to 180-day exclusivity in this case), 180-day exclusivity has been forfeited. According to Sandoz:Under the plain language of § 314.94(a)(12)(viii), once a Paragraph IV certification that had provided a basis for 180-day exclusivity rights is “amended,” 180-day exclusivity rights for that applicant, based on that patent in that certification, no longer exists.

ghts the complex connection between Orange Book listed use patents, the reference listed drug’s PI, and generic drug promotional labeling and other activities.Of particular note, the Federal Circuit’s decision leaves the validity of Teva’s estoppel defense in flux. Until this question is affirmatively answered, RLD sponsors’ assertions to FDA when listing patents in the Orange Book must be made carefully to avoid a potential equitable estoppel defense to an induced infringement action. Patents, especially method of use patents, must be carefully described in use codes when listing patents in the Orange Book via FDA Form 3542, and sponsors must claim each section of the labeling that contains protected information. These forms and assertions must also be kept current, particularly following subsequent approvals and labeling revisions.We will continue to monitor new cases that may arise related to pharmaceutical labeling carve-out regulations, and keep you informed of any legal updates. 21 CFR 314.94(a)(8)(iv). FDCA Sec. 505(j)(2)(A)(viii); 21 CFR 314.94(a)(12)(iii). There is a similar provision for 505(b)(2) applicants. See FDCA Sec. 505(b)(2)(B); 21 CFR 314.50(i)(1)(iii). 21 CFR 314.127(a)(7).[View source.]

The Best Pharmaceuticals for Children Act, 21 U.S.C. § 505A(o), permits the carve out of labeling protected only by patent and Hatch-Waxman exclusivity—and therefore provides no basis for carving out labeling protected by orphan drug exclusivity. FDA also possesses several other “general” carve-out authorities, see 21 C.F.R. §§ 314.94(a)(8)(iv), 314.127(a)(7), but those authorities are inapposite in light of FDA’s subsequently adopted pediatric-labeling rules and Congress’s enactment of section 505A(o). Indeed, prior to the passage of section 505A(o), FDA concluded that it lacked authority to carve out protected pediatric labeling in circumstances nearly identical to those presented here. FDA and the United States District Court for the District of Maryland concluded in the Otsuka litigation that FDA has authority to carve out pediatric labeling protected by orphan drug exclusivity.

FDA further states that EDTA is a component in several currently marketed drug products – some with higher quantities of EDTA than in “old” ACETADOTE – and concludes that “although there is a theoretical safety concern with EDTA in Acetadote . . . . we have insufficient evidence to conclude that the original formulation was withdrawn for reasons of safety.” Given FDA’s determination, as well as a waiver, granted pursuant to 21 C.F.R. § 314.99(b), of FDA’s so-called “exception excipient” regulations at 21 C.F.R. § 314.94(a)(9)(iii) for generic versions of injectable drug products that differ from the RLD in formulation (something other than a permitted difference in preservative, buffer, or antioxidant), FDA was able to approve InnoPharma’s ANDA No. 200644. As reflected in the more than 1,800-page administrative record, FDA’s decision on EDTA-containing Acetylcysteine Injection (captured in the Agency’s November 2012 Citizen petition response), was reached after significant debate within FDA. FDA’s Division of Gastroenterology and Inborn Errors Products (“Gastroenterology Division”) initially recommended in a July 1, 2011 memorandum that the Agency “not accept ANDAs for acetylcysteine injection based on the discontinued formulation” because of concerns about allergic reactions and syncope.

FDC Act § 505(j)(4)(H) states that FDA must approve an ANDA unless, among other things:information submitted in the application or any other information available to [FDA] shows that (i) the inactive ingredients of the drug are unsafe for use under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug, or (ii) the composition of the drug is unsafe under such conditions because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included.FDA’s regulations implementing FDC Act § 505(j)(4)(H), generally, are found in the Agency’s ANDA content and format regulations at 21 C.F.R. 314.94. Pertinent regulations on inactive ingredient changes for generic parenteral drug products are set forth in 21 C.F.R. § 314.94(a)(9).