ViroPharma Sues FDA Over Generic VANCOCIN; Alleges that FDA Violated the APA in Effectively Amending Bioequivalence Regulations

September 13, 2010

By Kurt R. Karst –   

It was not a question of whether ViroPharma Incorporated (“ViroPharma”) would sue FDA in connection with the approval of ANDAs for generic versions of the company’s antibiotic drug of last resort, VANCOCIN (vancomycin HCl) Capsules, but when.  In addition to a pending FOIA lawsuit (see our previous post here), ViroPharma has made voluminous submissions to FDA challenging the Agency’s draft bioequivalence recommendation for generic VANCOCIN, which provides that bioequivalence may be established based on comparative dissolution (i.e., in vitro information).  Last Friday we got the answer to the outstanding “when” question when ViroPharma sued FDA in the U.S. District Court for the District of Columbia. 

ViroPharma’s Complaint alleges that FDA violated the Administrative Procedure Act (“APA”) when the Agency failed to engage in notice-and-comment rulemaking “before effectively amending its [ANDA] regulations to permit a waiver of the in vivo bioequivalence requirement based on 21 C.F.R. § 320.24 even when none of the waiver criteria of 21 C.F .R. § 320.22 are satisfied.”  ViroPharma requests declaratory relief from the court, including “that the plain reading of FDA’s regulations requires an ANDA applicant seeking a waiver of the in vivo bioequivalence testing requirement to first meet one of the criteria set forth in 21 C.F.R. § 320.22,” and that a previous statement from FDA in a May 2008 response to a November 2007 citizen petition concerning generic PRECOSE (acarbose) – that 21 C.F.R. § 320.24 provides an independent basis for waiving the in vivo testing requirement even when none of the criteria of 21 C.F.R. § 320.22 is satisfied – constitutes an amendment to FDA’s ANDA bioequivalence regulations.

Under the FDC Act, as amended by the 2003 Medicare Modernization Act, for a drug, like vancomycin HCl, “that is not intended to be absorbed into the bloodstream, [FDA] may establish alternative, scientifically valid methods to show bioequivalence if the alternative methods are expected to detect a significant difference between the drug and the listed drug in safety and therapeutic effect” (FDC Act § 505(j)(8)(C)).  Although ANDAs often include the results of both in vivo and in vitro studies demonstrating bioequivalence to a reference listed drug, FDA’s ANDA regulations at 21 C.F.R. § 320.21 and § 320.22 provide that bioequivalence can be demonstrated through in vitro testing and that in vivo testing can be waived.  FDA’s regulations at 21 C.F.R. § 320.24 describe the types of in vivo and in vitro methods to establish bioequivalence. 

According to ViroPharma, “21 C.F.R. § 320.24 does not authorize the waiver of the in vivo bioequivalence requirement, which is the function of §§ 320.21 and 320.22.  Rather, § 320.24 lists the various methods for establishing either in vivo or in vitro bioequivalence, depending on which of those two types of testing is otherwise required by the regulations.”  And none of the circumstances identified in 21 C.F.R. § 320.22 apply to vancomycin HCl capsules, says ViroPharma:

[V]ancomycin capsules are not an injectable, topical or oral solution, or inhalation drug product (§ 320.22(b)); vancomycin is not a DESI drug (§ 320.22(c)); vancomycin capsule ANDAs do not seek approval of a different strength of a drug product that has already been approved (§ 320.22(d)(2); in vitro bioequivalence methods for vancomycin have not, to ViroPharma's knowledge, been shown to be correlated with in vivo data (§ 320.22(d)(3)); vancomycin capsule ANDAs do not seek approval for a reformulation of an already-approved product (§ 320.22(d)(4)); nor is there a need to approve vancomycin capsule ANDAs to ensure the continued marketing of a medically important drug product because Vancocin is readily available in the market (§ 320.22(e)).

When FDA issued its May 2008 PRECOSE citizen petition response, the Agency, according to ViroPharma, “claimed that under § 320.24 of its regulations, FDA has the discretion to accept in vitro studies for a nonsystemically absorbed drug product such as acarbose when such studies are determined to be a scientifically valid method of determining bioequivalence” (internal quotation omitted).   Thus, the Complaint argues that “[t]hrough this response, FDA effectively amended its regulations, which on their face plainly require that one of the waiver criteria of § 320.22 be satisfied before FDA can waive the in vivo requirement.  Instead, FDA interpreted the list of bioequivalence methods provided in 21 C.F.R. § 320.24 as a separate and sufficient regulatory basis for waiving in vivo bioequivalence requirements independent of 21 C.F.R. § 320.22.”

ViroPharma also points to FDA’s June 2010 Final Product Specific Bioequivalence Guidance as further evidence of this effective amendment of FDA’s ANDA bioequivalence regulations.  That final guidance states that “[f]or a drug that is not intended to be absorbed into the bloodstream, FDA may establish alternative methods to show bioequivalence that may be expected to detect a significant difference between the drug and the listed drug in safety and therapeutic effect (21 U.S.C. 355(j)(8)(C); 21 CFR 320.24)” [(emphasis in original)].  Thus, ViroPharma states:

In citing 21 C.F.R. § 320.24 in the Final Product Specific Bioequivalence Guidance as the sole regulatory basis for its decision to waive in vivo testing, FDA plainly ignored both the plain text of its own regulations and ViroPharma’s submissions explaining that one of the criteria of § 320.22 must first be satisfied in order for FDA to waive the in vivo bioequivalence testing requirement of § 320.21, and affirmed the rationale it enunciated in its Acarbose Bioequivalence Decision.

FDA’s alleged amendment to its ANDA bioequivalence regulations “increase[s] the likelihood of approvals for generic vancomycin ANDAs” – for which there are reportedly 11 ANDAs pending. 

Categories: Hatch-Waxman