US judge denies Sanofi-Aventis's bid to stop generic rival for Lovenox

A federal judge has denied Sanofi-Aventis 's request fora preliminary injunction that would have directed the US FDA to suspend and withdraw its approval of a generic version of Lovenox (enoxaparin sodium) from Sandoz (Novartis) and partner Momenta Pharmaceuticals, which has been on the market for several weeks. As a result of the ruling, sales of generic Lovenox will proceed.

In a 33-page opinion, Judge Emmet Sullivan of the US District Court for the District of Columbia said that the court found no reason to doubt the FDA's rationale for the ANDA approval and that given the deferential standard of review that the court must accord the FDA's scientific determinations, the court found it unlikely that Sanofi would succeed in its argument that the FDA's approval of generic enoxaparin is inconsistent with its past precedent.

Still, Sanofi-Aventis is not giving up its fight, claiming that the court has not ruled on the merits of the company's suit against the FDA. It said it would continue its legal battle, even without preliminary injunctive relief. However, a number of analysts believe that the judge's ruling leaves no door open for review.

Sanofi-Aventis sued the FDA in late July after the agency gave Sandoz approval for its ANDA. The French firm contended in its suit that the FDA had not followed its own regulations in granting the approval and had overstepped its authority by requiring ANDA applicants for enoxaparin to submit testing data relating to immunogenicity which was not contained in the original Lovenox application (scripintelligence.com, 28 July 2010). A hearing was later held to hear arguments (scripintelligence.com, 18 August 2010).

Judge Sullivan ruled that the FDA had not acted inappropriately in approving enoxaparin, and that the court "must defer to the FDA's interpretation of the FDCA [Food Drug & Cosmetic Act] as long as it is reasonable." He also noted that none of the parties had challenged the safety of the generic enoxaparin. He summed up by noting, "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." Additionally, he found Sanofi-Aventis's claims of irreparable harm from generic competition to be "a wash", since "whatever sales Sanofi will lose to Sandoz in the absence of an injunction, Sandoz will lose to Sanofi in the presence of one" and that Sanofi-Aventis had "failed to establish that the public interest favours interim injunctive relief". The ruling noted that Sandoz was expecting sales in the range of $40 million in the next six weeks.

The judge said that because the court found that Sanofi-Aventis was unlikely to establish that the FDA exceeded its authority in granting Sandoz's ANDA, "the court concludes that the public would be harmed by a court-ordered delay in the distribution of a generic that is approximately 30-35% cheaper than Lovenox".

judge counters all arguments

Sanofi-Aventis is challenging the FDA's approval of the ANDA as well as the FDA's 23 July response to a citizen's petition, in which the agency provided the five criteria (i.e., standards for identity) that an ANDA applicant needs to demonstrate "sameness" of its active ingredient as compared to Lovenox.

In court, Sanofi made three arguments as to why a preliminary injunction was necessary:

• The FDA exceeded its authority under the FD&C Act by requiring Sandoz to submit studies beyond what is permitted for ANDAs (i.e., immunogenicity studies that, according to Sanofi-Aventis, are studies "to demonstrate safety and effectiveness", rather than, as FDA argued, chemistry, manufacturing and controls information as a gauge of manufacturing purity);
• The FDA departed from agency precedent by approving a generic version of a drug derived from a complex biological starting material that has not yet been fully characterised; and
• The FDA approved generic enoxaparin without sufficient evidence that the drug product has the "same" active ingredient as Lovenox, as required by the ANDA provisions of the FD&C Act.

Judge Sullivan countered all of these arguments and sided with the FDA.

On the first argument, Judge Sullivan disagreed with Sanofi-Aventis that the FDA had overstepped its authority by asking Sandoz to perform additional safety tests before granting approval – tests to ensure that Sandoz's manufacturing processes and controls would not produce impurities with potential immunogenic effects to any greater degree than Lovenox itself.

He found "reasonable" the FDA's argument that its regulations "have long construed the statutory requirement of a 'full description' of manufacturing methods and controls…to include, among other things, detailed information related to the assessment of impurities". After noting that the FDA is entitled to a high level of deference within an area of its expertise, he concluded that Sanofi-Aventis was unlikely to demonstrate that the FDA exceeded its authority under the FD&C Act when it approved Sandoz's ANDA despite having required Sandoz to submit additional information not normally required of an ANDA.

The judge also countered the second argument on lack of characterisation. He said that the court found "persuasive" the FDA's explanation for its approach for determining "sameness" of enoxaparin (i.e., by considering the individual characteristics of the particular drug at issue). He added that the agency's decision to approve the generic was "based on the evaluation of complex scientific information within the agency's technical expertise" and entitled to deference by the court. The court found it unlikely that Sanofi would succeed in its argument that the FDA's approval of generic enoxaparin was inconsistent with its past precedent, he noted.

Finally, the judge found that the FDA had applied a reasonable "sameness" definition and that Sanofi-Aventis's third merits argument was unlikely to succeed. In addressing the issue of the FDA's answer to Sanofi-Aventis's citizen's petition, he wrote about the agency's "exhaustive response" to the arguments raised by the company. Specifically, he stated, "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…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 light of its determination that 'an ANDA applicant would not need to know [Sanofi's] exact manufacturing process parameters and conditions (e.g. depolymerisation time, pH, and temperature) to manufacture the same active ingredient'."

In his concluding remarks, Judge Sullivan stated, "This opinion does not foreclose the possibility that upon a more developed record, Sanofi may be able to establish that there are grounds for overturning the grant of Sandoz's ANDA. The court holds only that upon the current record, Sanofi has failed to establish that it meets the criteria for the grant of a preliminary injunction."

analyst reaction

Canaccord Genuity analysts maintain that the injunction denial "suggests a low chance of M-enoxaparin approval reversal"; M-enoxaparin is the name provided by Sandoz and Momenta for their generic version, which is the only current generic. Canaccord also predicts that Sanofi-Aventis will not launch an authorised generic while Sandoz's enoxaparin product is the sole approved generic.

Teva Pharmaceutical Industries and Amphastar also have pending ANDAs for enoxaparin at the FDA.