By Kurt R. Karst –
A Citizen Petition (Docket No. FDA-2013-P-0203) submitted to FDA earlier this year raises an issue that comes up from time to time – although not typically in a public forum – about the Agency’s so-called “exception excipient” regulations applicable to sponsors of ANDAs for generic versions of brand-name drugs that differ from the Reference Listed Drug (“RLD”) formulation in certain ways. Ever since FDA finalized its ANDA regulations in the early 1990s and drafted its Interim Inactive Ingredients Policy in 1994 (which is not specifically cited in FDA decisions, and, while apparently abandoned, still reflects general Agency policy), the Agency has been rather inflexible in applying the regulations. We previously authored an article for the Washington Legal Foundation – “The Drug User Fee Catch-22” – arguing that FDA should be more flexible in receiving and approving ANDAs for drug products whose formulations differ from that of the RLD. And now FDA is being asked to do so more formally in the context of a generic version of VFEND IV (voriconazole) for Injection 200 mg/vial. 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. [(Emphasis added)]
Preservative, buffer, and antioxidant changes in generic parenteral drug products are referred to as “exception excipients,” which may qualitatively or quantatively differ from the RLD formulation. Other regulations at 21 C.F.R. § 314.94(a)(9)(iv) identify exception excipients for generic ophthalmic and otic drug products (i.e., preservative, buffer, substance to adjust tonicity, and thickening agent). Excipients not identified in these regulations are referred to as “non-exception excipients.”
FDA’s exception excipient regulations at 21 C.F.R. § 314.94(a)(9) find their parallel in 21 C.F.R. § 314.127(a)(8)(ii), which addresses the grounds for an FDA refusal to approve an ANDA for a parenteral, ophthalmic, or otic drug product. For example, 21 C.F.R. § 314.127(a)(8)(ii)(B) states: “FDA will consider an inactive ingredient in, or the composition of, a drug product intended for parenteral use to be unsafe and will refuse to approve the [ANDA] unless it contains the same inactive ingredients, other than preservatives, buffers, and antioxidants, in the same concentration as the listed drug. . .” (emphasis added).
FDA has not provided a thorough explanation as to the basis for its exception excipient regulations. In a recent citizen petition decision (Docket No. FDA-2006-P-0007, at pages 57-58) concerning vancomycin, FDA commented that the Agency “has more stringent limitations on inactive ingredients to account for the fact that each of these drug products represents an individual pharmaceutical system with its own characteristics and requirements, and that inactive ingredients are added to maintain these systems.”
Notwithstanding FDA’s exception excipient regulations, the Agency has, on occasion, but only in very limited circumstances, waived these regulations pursuant to 21 C.F.R. § 314.99(b) to permit the receipt and approval of an ANDA for a drug product containing a non-exception excipient change from the RLD. Historically, FDA policy limits granting such waivers to cases in which an ANDA applicant seeks approval to market a drug product containing a non-exception excipient used in a discontinued, brand-name RLD formulation that is not used in the currently-marketed RLD formulation. For example, FDA has granted waivers in the cases of generic ZOSYN (piperacillin sodium; tazobactam sodium) Injection (Docket Nos. FDA-2005-P-0003, FDA-2006-P-0019, FDA-2006-P-0331, and FDA-2006-P-0391), generic SANDOSTATIN (octreotide acetate) Injection (Docket Nos. FDA-2001-P-0121 and FDA-2005-P-0370), and generic ACETADOTE (acetylcysteine) Injection (Docket No. FDA-2012-P-0507). FDA’s approval of generic ZOSYN was challenged in court and upheld (see our previous posts here and here). Late last year, FDA’s approval of generic ACETADOTE was challenged in court (see our previous post here). The case has been briefed (copies of the briefs are available here, here, here, and here) and a decision is pending. This is the only situation in which FDA will entertain a waiver of the Agency’s excipient regulations. Indeed, a few years ago, FDA stated just that in correspondence to one ANDA sponsor: “The only situation in which the FDA will entertain a waiver of the requirement under 21 CFR 314.94(a)(9)(iii) . . . is when the [RLD] has changed its formulation and has discontinued the previous formulation for reasons other than safety and/or effectiveness.” (Emphasis added).
Manufacturers unable to obtain a waiver for a non-exception excipient change are effectively forced to submit a 505(b)(2) NDA. While such products may be A-rated in the Orange Book once approved, and, therefore, are considered substitutable for the brand-name listed drug relied on for approval (e.g., Nicardpine HCl, NDA No. 022276; Oxaliplatin, NDA No. 022160; Docetaxel, NDA Nos. 201195, 022312, 022234, 201525; and Pamidronate Dosodium, NDA No. 021113), 505(b)(2) applications are subject to significantly higher user fees under PDUFA compared to ANDAs under GDUFA. We also note that two pending Citizen Petitions (Docket Nos. FDA-2011-P-0610 and FDA-2013-P-0371; see our previous post here) request that FDA create a rulemaking process for 505(b)(2) NDA therapeutic equivalence rating decisions.
The recent Citizen Petition requesting that FDA refrain from enforcing its exception excipient regulations for generic parenteral drug product formulations to permit a non-exception excipient change vis-à-vis the formulation of VFEND – i.e., a change in solubilizing agent from SBEβCD to HPβCD – argues that compliance with the non-exception excipient requirements is unnecessary, and that a wealth of scientific information justifies a waiver of the regulations. Referring to FDA’s petition decisions on generic ZOSYN and SANDOSTATIN formulatins, the petitioner states:
The petitioner recognizes that [FDA’s previous] decisions were based on petitions in which the petitioners sought approval to submit ANDAs based on discontinued formulations of previously-approved RLDs . . . . Nonetheless, the agency’s decision in those petitions demonstrates that the agency can consider an ANDA drug product to be safe even though it contains a different inactive ingredient (other than preservatives, buffers, or antioxidants) from the current RLD. The petitioner believes that, even though the inactive ingredient in its proposed formulation of Voriconazole for Injection 200 mg/vial was not part of a previously-approved voriconazole formulation, there is sufficient data to prove the safety of its proposed formulation and its eligibility for ANDA submission relying on Vfend I.V. as the RLD.
Furthermore, the petitioner believes that its proposed formulation is as effective as the RLD, and would meet requirements for ANDA approval pursuant to FDA’s grant of this petition for ANDA submission. . . .
In an interesting twist, the petition also argues that “publicly-available information in the Vfend I.V. NDA shows that in Pfizer’s early development program (starting in 1991) its intravenous voriconazole was formulated with HPβCD,” and that “SBEβCD as a solubilizing excipient began to be used in Pfizer’s intravenous formulation in clinical trials beginning in 1994, and the FDA apparently permitted Pfizer to change the inactive ingredient in its formulation from HPβCD to SBEβCD without requiring bioequivalence studies between those two formulations.” According to the petitioner, “[t]his implies that the data available within the Vfend NDA submission support the petitioner’s claim that efficacy of the drug will not be affected by changing the solubilizing agents.”
While all of the information provided in the petition to support a waiver of FDA’s exception excipient regulations is quite interesting, we’re reminded of FDA’s statement to an ANDA sponsor that, to our understanding, still reflects Agency policy: “The only situation in which the FDA will entertain a waiver of the requirement under 21 CFR 314.94(a)(9)(iii) . . . is when the [RLD] has changed its formulation and has discontinued the previous formulation for reasons other than safety and/or effectiveness.”