D.C. District Court Denies Preliminary Injunction in Generic LOVENOX Case; Is the Juice Worth the Squeeze for Sanofi to Appeal?

By Kurt R. Karst –   

When we attended the August 17th hearing in Sanofi-aventis U.S. L.L.C.’s (“Sanofi’s”)  challenge to FDA’s July 23, 2010 approval of Sandoz Inc.’s (“Sandoz’s”) ANDA No. 77-857 for a generic version of Sanofi’s LOVENOX (enoxaparin sodium injection), it seemed as though Judge Emmet G. Sullivan of the U.S. District Court for the District of Columbia was leaning towards denying Sanofi’s Motion for Preliminary Injunction.  And as one member of the Food and Drug Bar pointed out to us, the Scales of Justice directly behind Judge Sullivan were literally tilted ever so slightly in favor of the defense table.  That observation now appears to have been prescient, as Judge Sullivan denied Sanofi’s motion in a 33-page opinion handed down late on August 25th.

As we previously reported (here and here), Sanofi sued FDA on July 26th requesting that the court issue a declaratory judgment that FDA acted unlawfully in approving ANDA No. 77-857, 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.  (Sanofi later agreed to consolidate its temporary restraining order request with its preliminary injunction request.)  In addition to the approval of ANDA No. 77-857, Sanofi also challenged FDA’s July 23rd response to a 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.

Sanofi set forth in its papers three merits arguments as to why a preliminary injunction is necessary: (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. 77-857 when the product has not yet been fully characterized; and (3) FDA approved ANDA No. 77-857 without sufficient evidence that the drug product has the “same” active ingredient as LOVENOX (as required by FDC Act § 505(j)(2)(A)).  FDA addressed each of these arguments in its Opposition and Surreply briefs (Sanofi Reply brief here), as did Sandoz in its Opposition brief.  (AARP also submitted an amicus brief in the case.)

With respect to Sanofi’s first merits argument, the company argued that under the familiar Chevron analysis, the case should be resolved at Step One, because FDC Act § 505(j)(2)(A) “unambiguously prohibits FDA from requiring an ANDA applicant to conduct basic safety testing such as immunogenicity testing.”  Judge Sullivan disagreed, however, stating that:

The statute itself says nothing about the type of “full description” an ANDA applicant must submit in order to satisfy the FDA that the chemistry, manufacturing, and controls of the generic drug producer are sufficient to ensure the purity of the proposed drug product.  It says only that the full description must allow the FDA to determine that “the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug are [not] inadequate to assure and preserve its identity, strength, quality, and purity[.]”

Thus, according to Judge Sullivan, the proper analysis is under Chevron Step Two, where “this Court must defer to the FDA’s interpretation of the FDCA as long as it [is] reasonable. . . .”  And under that inquiry, Judge Sullivan ruled that:

FDA’s construction of the FDCA as permitting the agency to request information to assess whether impurities resulting from a generic drug producer’s manufacturing processes and controls would generate a greater immune response than the [Reference Listed Drug] is both reasonable and consistent with its regulations.  Moreover, because the FDA’s determination of what is required to assess the “purity” of a generic drug for purposes of the FDCA “rests on the ‘agency’s evaluations of scientific data within its area of expertise,’” it is “entitled to a ‘high level of deference’ from this court.”  Accordingly, the Court concludes that Sanofi is unlikely to demonstrate that the FDA exceeded its authority under the FDCA when it approved Sandoz’s ANDA despite having required Sandoz to submit additional information comparing the impurity profiles of its generic enoxaparin with Lovenox. [(citations omitted)]

With respect to Sanofi’s second merits argument – that FDA’s approval of ANDA No. 77-857 “represents a significant departure” from precedent concerning generic versions of drug products that, like enoxaparin, are derived from a complex starting material that has not been fully characterized (e.g. hyaluronidase, somatropin, and conjugated estrogens) and violates the Administrative Procedure Act (“APA”) – Judge Sullivan ruled that it is “unlikely that Sanofi will succeed in its argument that the FDA’s approval of generic enoxaparin is inconsistent with its past precedent.”  Citing the U.S. District Court for the District of Columbia’s 1997 decision in Bracco Diagnostics, Inc. v. Shalala, 963 F. Supp. 20 (D.D.C. 1997), in which the court ruled that “an agency must treat similar cases in a similar manner unless it can provide a legitimate reason for failing to do so,” Judge Sullivan stated that “the FDA provided ‘legitimate reason[s]’ for deciding that enoxaparin should be treated differently than the drugs cited by Sanofi.”

Finally, with respect to Sanofi’s “sameness” argument – that FDA violated the APA when the Agency “ignored voluminous scientific evidence demonstrating that until enoxaparin is fully characterized, generic enoxaparin products that do not use a manufacturing process that is equivalent to [Sanofi’s] process will not be the same as Lovenox,” and when FDA failed to provide a “rational explanation for its decision to disregard scientific evidence that directly contradicts its administrative findings” – Judge Sullivan found that FDA applied a reasonable “sameness” definition and that Sanofi’s third merits argument is unlikely to succeed.  According to Judge Sullivan:

While Sanofi may not agree with the FDA’s determination that an ANDA applicant for enoxaparin can demonstrate sameness by satisfying the five-part test discussed [in FDA’s citizen petition response], the Court concludes that the FDA’s definition of “sameness,” as applied to enoxaparin products, is reasonable. . . .   It was similarly reasonable for the FDA to conclude that an ANDA applicant need not use the same manufacturing process as Sanofi . . . .  

In sum, just because the FDA – after seven years of careful consideration of Sanofi’s citizen petition and five years of examination of Sandoz’s ANDA – reached a conclusion at odds with the position advanced by Sanofi, does not mean that the FDA’s decision was arbitrary and capricious.  To the contrary, a review of the FDA’s response to Sanofi’s citizen petition demonstrates that the FDA “‘examine[d] the relevant data and articulate[d] a satisfactory explanation for its decision.’” [(citations omitted)]

Now the question on everyone’s mind is whether Sanofi will appeal Judge Sullivan’s ruling.  We think there is a reasonable likelihood that an appeal is coming . . . and we’ll let you know if that happens.  But FDA’s track record in these types of APA challenges does not bode well for Sanofi.