DC District Court Grants FDA Summary Judgment in Generic LOVENOX Dispute

By Kurt R. Karst –

On February 7, 2012, Judge Amy Berman Jackson of the U.S. District Court for the District of Columbia issued her decisionin the long-running dispute concerning FDA’s July 23, 2010 approval of Sandoz Inc.’s (“Sandoz’s”) ANDA No. 077857 for a generic version of Sanofi-aventis U.S. L.L.C.’s (“Sanofi’s”) anti-coagulant drug LOVENOX (enoxaparin sodium injection). Concluding that FDA’s (1) “request for immunogenicity data in Sandoz’s ANDA was both lawful and reasonable;” (2) “approval of the drug did not constitute an arbitrary departure from agency precedent;” and (3) “determination of active ingredient sameness was [reasonable],” Judge Jackson granted Motions for Summary Judgment filed by FDA and intervenor Sandoz (here and here) and denied Sanofi’s Cross-Motion for Summary Judgment. The 33-page decision may have important implications on future lawsuits involving the approval of generic versions of complex drug products, and perhaps even biosimilars.

As folks might recall, Sanofi initially filed a Complaint and a Motion for Temporary Restraining Order and Preliminary Injunction late on July 26, 2010 requesting that the court issue a declaratory judgment that FDA acted unlawfully in approving ANDA No. 077857, as well as a temporary restraining order and preliminary injunction directing FDA to immediately suspend and withdraw approval of the Sandoz ANDA, and a permanent injunction under the same terms (see our previous post here). On the same day that FDA approved Sandoz’s ANDA, the Agency responded to a February 2003 Sanofi citizen petition in which the Agency outlined five criteria (i.e., standards for identity) that an ANDA applicant needs to demonstrate sameness of its active ingredient as compared to LOVENOX (see our previous post here).(FDA has subsequently indicated that the Agency might be considering applying similar criteria to another complex drug product, as well as biosimilars.)

Judge Emmet G. Sullivan, who was originally assigned the case, denied Sanofi’s motion in an opinion handed down on August 25, 2010 (see our previous post here). Several months later, Sanofi filed its Motion for Summary Judgment (see our previous post here) arguing three points:

(1) FDA exceeded its authority under the FDC Act (specifically FDC Act § 505(j)(2)(A)) by requiring Sandoz to submit studies beyond what is permitted for ANDAs (i.e., immunogenicity studies that, according to Sanofi, are studies intended “to demonstrate safety and effectiveness,” rather than, as FDA argued, chemistry, manufacturing, and control information);

(2) FDA departed from Agency precedent by approving ANDA No. 077857 when the product has not yet been fully characterized; and

(3) FDA approved ANDA No. 077857 without sufficient evidence that the drug product has the “same” active ingredient as LOVENOX (as required by FDC Act § 505(j)(2)(A)).

Judge Jackson ruled that each issue can be decided on summary judgment as a pure question of statutory interpretation or a pure question of law.

Did FDA exceed its authority under the FDC Act by requiring Sandoz to submit immunogenicity data as part of its ANDA? Analyzing this issue under the familiar two-step Chevron analysis, the court ultimately agreed with FDA that the Agency has the authority to interpret the “full description” requirement of FDC Act § 505(b)(1)(D) to encompass the information FDA requires to make the findings required by FDC Act § 505(j)(4)(A) specific to ANDAs, such as immunogenicity data, stating:

Through the ANDA pathway’s specific embrace of the NDA requirements, and the imposition of the clear demands in [FDC Act § 505(j)(4)(A)], Congress rendered the ANDA requirements to be ambiguous and open to agency interpretation, and not as restrictive as the plaintiffs describe them to be. By specifically incorporating [FDC Act § 505(b)(1)(D)] into the ANDA requirements, Congress gave FDA the authority to utilize its expertise to determine what information it needs to make the assessment it is required to make under [FDC Act § 505(j)(4)(A)].

Citing D.C. Circuit precedent, Judge Jackson noted that the Court’s observations in Serono Labs., Inc. v. Shalala, 158 F.3d 1313 (D.C. Cir. 1998), “express a clear view that [FDC Act § 505(j)(2)(A)] does not limit the agency’s freedom to determine what kinds of information will be needed to fulfill the listed ANDA requirements.” Moreover, writes Judge Jackson, an analysis of the statutory text both in light of the entire statutory scheme and the statute’s purpose suggest that FDC Act § 505(b)(1)(D) applicable to NDAs and included by reference in FDC Act § 505(j)(2)(A) applicable to ANDAs is ambiguous, and therefore, cannot be decided at Chevron Step I.

Moving on to Chevron Step II, the court agreed with the determination Judge Sullivan made in connection with his August 25, 2010 decision that FDA’s interpretation of the statute to include immunogenicity testing was reasonable.

According FDA the deference required under Serono to make its own determination about the information it might need, the Court finds that FDA’s interpretation of the ANDA approval regime was reasonable, and that it was reasonable for the agency to conclude that immunogenicity studies are encompassed by the “full description” described in [FDC Act § 505(b)(1)(D)]. The potential for the generic drug to elicit a different adverse response than the parent could be the result of impurities, which in turn result from the methods, facilities, and controls used to manufacture, process, and pack a drug. By revealing what impurities remain at the end of that process, the studies shed light on, or indirectly “describe,” those methods and controls.

Did FDA depart from Agency precedent by approving a generic drug that is not fully characterized? Giving short schrift to this argument, Judge Jackson specifically incorporates Judge Sullivan’s analysis of this issue from his August 25, 2010 decision, and writes that “[i]n making its decision to approve Sandoz’s drug before it was fully characterized, FDA ‘provided ‘legitimate reason[s]’ for deciding that enoxaparin should be treated differently than the drugs cited by Sanofi’ [(i.e., Premarin, Hyaluronidase, and Omnitrope)] and therefore satisfied the minimal standard of rationality required.” Judge Jackson also expresses some skepticism that the Premarin, Hyaluronidase, and Omnitrope precedents in which FDA would not accept an ANDA “rise to the sort of precedent from which a departure needs to be justified,” but she further notes that the court “does not reach that question since the decision and the manner in which [FDA] diverged from previous decisions were adequately explained in this instance.”

Did FDA sufficiently prove that Sandoz’s generic enoxaparin has the same active ingredient as Lovenox? Here, arguments focused on the five criteria FDA laid out in the Agency’s citizen petition response that an ANDA applicant needs to demonstrate sameness of its active ingredient as compared to LOVENOX: (1) equivalence of physicochemical properties; (2) equivalence of heparin source material and mode of depolyierization; (3) equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species; (4) equivalence in biological and biochemical assays; and (5) equivalence of in vivo pharacodynamic profile.

Instead of focusing on any one criterion, Judge Jackson focused on whether all five, overlapping criteria, when considered together, provided “a reasonable way for FDA to determine active ingredient sameness.” “Not only did FDA support its approach in a thorough, well-reasoned response to Sanofi’s citizen petition, but it also carefully considered both sides of the argument internally – to settle the internal dispute over the validity of the five-pronged test – before doing so. . . . While fully characterizing enoxaparin would have been another reasonable, or perhaps even more reasonable, way to determine active ingredient sameness, the Court is satisfied that the five-pronged approach FDA used was reasonable,” concludes Judge Jackson.