Draft FDA guidance generally defines the term “duplicate” to mean:drug products that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, in identical dosage forms, but not necessarily containing the same inactive ingredients, and that 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.Elsewhere,FDA has stated that the word “duplicate” means “a product that is the same as the listed drug with respect to active ingredient, dosage form, route of administration, strength, and conditions of use, among other characteristics.”FDA’s regulation at 21 C.F.R. § 314.101(d)(9) states that “FDA may refuse to file an application if . . . . [t]he application is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the act.” 21 C.F.R. § 314.101(d)(9).

aph VI certification to a patent or patent claim for which an ANDA applicant previously submitted a paragraph IV certification is a “recertification” rather than an “amendment” of the paragraph IV certification (see section V.F.3).Requires that if an amendment to the ANDA 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 V.F.1).21 C.F.R. § 314.97 Patent certification requirements (§ 314.97(c))Omits proposed § 314.97(c) on patent certification requirements for ANDA supplements, which is not being finalized at this time (see section V.F.2).21 C.F.R. § 314.99Other responsibilities of an applicant of an ANDA (§ 314.99)No substantive changes from the proposed rule (see section V.L.).21 C.F.R. § 314.101 Receiving an ANDA (§ 314.101(b))Clarifies current Agency practice that following a refuse-to-receive decision, an ANDA applicant may: Withdraw the ANDA under § 314.99; correct the deficiencies and resubmit the ANDA; or take no action, in which case FDA may consider the ANDA withdrawn after 1 year (see section V.J.2).Omits the proposed administrative consequence for ANDA applicants who fail to send notice of paragraph IV certification within the statutory timeframe (see section V.J.3).NDA or ANDA deficiencies (§ 314.101(d))Clarifies that FDA will consider the nature (e.g., major or minor) of the deficiencies, including the number of deficiencies in the ANDA in determining whether an ANDA is incomplete on Its face (see section V.J.2).Regulatory Deficiencies (§ 314.101(e))Clarifies that FDA will refuse to file a 505(bX2) application or refuse to receive an ANDA if submission is not permitted under sections 505(c)(3)(E)(ii), 505(j)(5)(F)(ii), 505A(b)(1)(A)(i)(I), 505A(c)(1)(A)(i)(I), or 5

Enter FDA’s intervening NDA approval policy. . . .FDA’s regulation at 21 C.F.R. § 314.101(d)(9) states that “FDA may refuse to file an application if . . . . [t]he application is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the act.” 21 C.F.R. § 314.101(d)(9).

That is, even if a drug product is manufactured using the same formula, same equipment, and at the same facility as an already-approved product, FDA has required the new applicant to perform some level of bioequivalence testing, at a minimum, to support approval.Although companies have requested FDA to permit them to reference already-approved bioequivalence data, FDA has for decades rejected such requests on the basis of 21 C.F.R. § 314.101(d)(8). This regulation states that FDA will refuse to receive an application if:The drug product that is the subject of the submission is already covered by an approved application or abbreviated application and the applicant of the submission:(i) Has an approved application or abbreviated application for the same drug product; or(ii) Is merely a distributor and/or repackager of the already approved drug product.

17 FDA, FDA Drug Competition Action Plan (updated Dec. 21, 2020), https://www.fda.gov/drugs/guidance-compliance-regulatory-information/fda-drug-competition-action-plan.18 FD&C Act § 505(j)(2)(A)(iv), 21 U.S.C. § 355(j)(2)(A)(v)); 21 C.F.R. §§ 314.101, 314.127; see also FDA Fact Sheet, What’s Involved In Reviewing And Approving Generic Drug Applications? (undated), https://www.fda.gov/media/99163/download.

That instance appears to have been a one-off for FDA. “Ultimately, the question comes down to whether, in each individual case, the applicant has provided sufficient information for the agency to commence its substantive review,” wrote Judge Kollar-Kotelly.Interestingly, Judge Kollar-Kotelly notes in her Opinion, and which FDA raised in the Agency Motion for Summary Judgment, that Boehringer did not avail itself of the opportunity – see 21 C.F.R. § 314.101(a)(3) – to have the PRADAXA NDA filed over protest and reviewed by FDA. Instead, the company accepted FDA’s refuse-to-file letter and responded to the deficiencies identified therein a couple of months later, after which FDA accepted the NDA as filed. In hindsight, would that have been the better option?

Accordingly, no application is considered to be “initially submitted” if it has not been found to be sufficiently complete to meet the filing requirement for an application.Interestingly, FDA says that BIPI had the chance to secure a date earlier than April 19, 2010 as the date of initial submission, but lost it when the company decided not to raise the rarely used “filing over protest procedures” at 21 C.F.R. § 314.101(a)(3). According to FDA:While BI had an opportunity, under FDA regulations, to contest FDA’s position, assert that its application was in fact sufficiently complete to be reviewed, and ask FDA to file the application over protest, BI did not do so. FDA accordingly refunded 75% of the user fee for this application and awaited submission of additional and corrected data that would permit the application to be considered suffrciently complete such that FDA review of the entire application could commence.

This regulation at 21 CFR 314.95(c)(1) sets forth the requirement that the notice include “a statement that FDA has received an [ANDA] submitted by the applicant.” FDA’s regulation at 21 CFR 314.101(b)(1) defines the term “received.” It states that “An [ANDA] will be reviewed after it is submitted to determine whether the [ANDA] may be received.

By Kurt R. Karst – A recent report from Leerink Swann LLC analyst Howard Liang, Ph.D. suggests that what appears to be a recent increase in the number of Refuse-to-File (“RTF”) letters issued by FDA to NDA and BLA sponsors – some of which are large, experienced biotech companies – might signal both a greater willingness from FDA to issue such decisions, and therefore a higher filing threshold, and that filing decisions are no longer non-events. FDA’s regulations at 21 C.F.R. § 314.101 (drugs) and 21 C.F.R. § 601.2 (biologics) provide the bases for the Agency to RTF an application – generally because an application does not, on its face, contain information required under the FDC Act, under the PHS Act, or in FDA’s implementing regulations. (Note that NDA/BLA deficiencies that serve as the basis for an RTF action are distinct from filing review issues, which pertain only to applications that have been filed.)