[1]This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. [2]An ANDA includes all amendments and supplements to the application. 21 CFR 314.3(b). FDA recently revised certain regulations in parts 314 and 320 and this guidance refers to the regulations as revised. See Abbreviated New Drug Applications and 505(b)(2) Applications; Final Rule, 81 FR 69580 (October 6, 2016). [3]Throughout this guidance we use the term generic drug to refer to a new drug product described in an ANDA submitted under section 505(j) of the FD C Act. [4]21 CFR 314.94(a)(3). [5]Section 505(b)(1) of the FD C Act. [6]Section 505(j)(2)(A), (j)(2)(C), and (j)(4) of the FD C Act; see also 21 CFR 314.94(a). [7]Section 505(j)(2)(A)(iv) of the FD C Act. [8]Section 505(j)(2)(A)(vi) of the FD C Act. [9]See 21 CFR 314.3(b). Pharmaceutical equivalents are drug products in identical dosage forms and route(s) of administration that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of modified-release dosage forms that require a reservoir or overage or such forms as prefilled syringes where residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing period; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates. See 21 CFR 314.3(b). [10]Section 505(j)(2)(C) of the FD C Act; 21 CFR 314.93(b). [11]21 CFR 314.93(e)(1)(i). [12]21 CFR 314.3(b); see also section 505(j)(7) of the FD C Act. [13]21 CFR 314.3(b). [14]The Orange Book is available at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm. [15]An applicant must report its withdrawal of a listed drug from sale within 15 working days of the withdrawal. 21 CFR 314.81(b)(3)(iv). [16]An applicant may request that approval of an NDA or ANDA be withdrawn because the drug product that is the subject of the NDA or ANDA is no longer being marketed. 21 CFR 314.150(c). FDA will withdraw approval of the NDA or ANDA based on the applicant’s request provided none of the conditions in 314.150(a) or (b) applies. [17]Section 505(j)(2) of the FD C Act; 21 CFR 314.94(a)(3). [18]21 CFR 314.3(b). There may be multiple approved drugs each of which may be eligible to be an RLD for a particular drug product, e.g., either Trandate 100 mg tablets (NDA 018716) or Normodyne 100 mg tablets (NDA 018687) are eligible to be the RLD for an ANDA for Labetalol Hydrochloride 100 mg tablets. [19]The principles in this draft guidance focus on the appropriate identification of products referred to in ANDAs for generic drugs that are intended to duplicate listed drugs approved after enactment of the Drug Price Competition and Patent Term Restoration Act of 1984 (Pub.L. 98-417), commonly referred to as the Hatch-Waxman Amendments. If an applicant is seeking approval of an ANDA that is intended to duplicate a listed drug approved prior to enactment of the Hatch-Waxman Amendments, the applicant may consult the Agency if it has questions regarding appropriate identification of products. [20]21 CFR 314.161(a). [21]See, e.g., Determination that KENALOG (Triamcinolone Acetonide) Lotion and Other Drug Products Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness (81 FR 13797; March 15, 2016); and Determination that Ondansetron (Ondansetron Hydrochloride) Injection, USP, in PL 2408 Plastic Container, 32 Milligrams in 50 Milliliters, Was Withdrawn From Sale for Reasons of Safety or Effectiveness (80 FR 32962; June 10, 2015). [22]The Orange Book may not include notations for all such determinations and does not reflect determinations made before 1995. A potential applicant should refer to the Federal Register to see if FDA has made a determination about whether a listed drug has been voluntarily withdrawn from sale for safety or effectiveness reasons. [23]21 CFR 314.162(a). [24]See FDA’s guidance for industry on Controlled Correspondence Related to Generic Drug Development (Sept. 2015). [25]21 CFR 314.122(a). If the listed drug is moved to the Discontinued Section while the ANDA is pending, a safety and effectiveness determination must be made by FDA before the ANDA can be approved. 21 CFR 314.161(a)(1). [26]21 CFR 314.122(a). [27]The FD C Act and FDA’s regulations permit labeling differences because of differences approved under a suitability petition or because the generic drug and the RLD are produced or distributed by different manufacturers. Section 505(j)(4)(G) of the FD C Act and 21 CFR 314.94(a)(8)(iv). In certain instances, the labeling for the generic drug may differ from the labeling for the RLD if FDA permits the ANDA applicant to omit (carve out) protected conditions of use from labeling and obtain approval for conditions of use that are not covered by unexpired patents or exclusivity. See, e.g., Section 505(j)(2)(A)(viii) of the FD C Act; 21 CFR 314.127(a)(7). [28]An applicant is responsible for checking appropriate sources in order to obtain the RLD labeling. In instances where the RLD labeling cannot be located, an applicant for convenience initially may compare its proposed generic drug’s labeling with the labeling of another ANDA that referenced the same RLD and currently is marketed. Prior to approval, the applicant may need to revise labeling to reflect certain updated information that would have been necessary had the RLD not been withdrawn. See FDA’s draft guidance for industry on Updating ANDA Labeling After the Marketing Application for the Reference Listed Drug Has Been Withdrawn (July 2016). [29]21 CFR 314.94(a)(3)(i). [30]Section 505(j)(2)(D) of the FD C Act; 21 CFR 314.96(c). We note that where an applicant has previously mistakenly identified the reference standard (described in detail in section III.C.) as the RLD on FDA Form 356h or elsewhere in its ANDA, the applicant may submit an amendment to a pending ANDA or a supplement to an approved ANDA to correct the information. FDA considers this error to be a deficiency related to identification of the appropriate listed drug as the RLD, rather than a change in the RLD itself. The cover letter for such a submission should clearly identify that the purpose of the submission is “Correction of RLD information.” [31]Section 505(j)(2)(D)(i) of the FD C Act. See also 21 CFR 314.96(c). [32]Section 505(j)(2)(A)(iv) of the FD C Act. [33]21 CFR 320.24. [34]21 CFR 314.3(b). We note that in vivo bioequivalence evidence is not required in all circumstances, see, e.g., 21 CFR 320.22 and 320.24(b)(6). When in vivo bioequivalence testing is required or an applicant otherwise seeks to support a demonstration of bioequivalence with in vivo data, such testing should be conducted with the drug product FDA selects as the reference standard. [35]An ANDA applicant may use the authorized generic version of the RLD as the reference standard for purposes of conducting an in vivo bioequivalence study required for approval. See section 505(t) of the FD C Act for additional information on authorized generics. [36]See Abbreviated New Drug Applications and 505(b)(2) Applications; Final Rule, 81 FR 69619 (October 6, 2016). There may be instances in which the highest strength would not be the appropriate reference standard for testing in vivo bioequivalence. For example, FDA may select a different strength if testing at that different strength provides greater assurance of safety for the subject, is more feasible in terms of recruiting subjects who meet the study criteria, or is necessary to detect differences in effect. Further, applicants may submit a citizen petition to FDA requesting that FDA reconsider the strength selected for in vivo testing if, for example, clinical patterns of use of the drug product support use of a strength that differs from that selected by FDA as the reference standard. [37]When FDA has made a determination that a listed drug has been withdrawn from sale for reasons of safety or effectiveness, the Agency will not select a new reference standard because the RLD will be removed from the Orange Book (and any ANDAs referencing that RLD will generally also be removed from the Orange Book). [38]Executive Order 13588 on reducing prescription drug shortages was issued on October 21, 2011, and directs FDA to take steps to help prevent and reduce current and future disruptions in the supply of lifesaving drug products. For example, in June 2013, FDA removed Doxil as the reference standard for doxorubicin HCl liposome injection and selected Lipodox (ANDA 203263) as the reference standard. The shortage and continued unavailability of Doxil (NDA 050718), a lifesaving drug product for cancer treatment, meant that there existed no available reference standard against which to test a generic doxorubicin HCl liposome injection product, effectively shielding Doxil from further generic competition. [39]See generally, guidance for industry on Bioequivalence Recommendations for Specific Products (June 2010). [40]See the discussion above regarding designation of an additional RLD to ensure that a pharmaceutically equivalent drug product approved in an NDA is not shielded from generic competition. [41]See, e.g., Section 505(j)(2)(B) of the FD C Act; 21 CFR 314.94(a)(12). [42]21 CFR 314.94(a)(3). [43]FDA previously has indicated that for drug products for which one NDA holder holds multiple approved NDAs for different strengths of the same drug product, it may be appropriate to accept an ANDA that References more than one NDA number. This promotes a more efficient use of the Agency’s review resources. See guidance for industry on Variations in Drug Products that May Be Included in a Single ANDA (Dec. 1998). [44]See Comprehensive Table of Contents Headings and Hierarchy, http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM315023.pdf, for electronic submissions. [45]See, e.g., OGD’s ANDA Filing Checklist, which provides technical information on how to organize an ANDA submission. [46]See discussion of suitability petitions in the Background section of this guidance. [47]21 CFR 314.94(a)(3)(i) and (iii). [48]21 CFR 314.93(f)(2). See also Abbreviated New Drug Applications and 505(b)(2) Applications; Final Rule, 81 FR 69621-69622 (October 6, 2016) (FDA finalized the requirement that an applicant with a pending ANDA subject to an approved suitability petition must change its RLD upon FDA approval of an NDA for the same drug product described in the approved suitability petition. This decision reflects the Agency’s judgment that “considerations regarding an ANDA’s limited reliance on an approved suitability petition are outweighed by the need for a clear determination of therapeutic equivalence for a generic drug product and protection of intellectual property rights accorded an NDA holder.”)
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