FDA approval of Sandoz Inc. and Momenta Pharmaceuticals Inc.’s Glatopa (glatiramer), the first generic of Teva Pharmaceutical Industries Ltd.’s Copaxone, came with a road map for demonstrating active ingredient sameness to the structurally complex multiple sclerosis drug.

The agency disagreed with Teva’s arguments in a series of citizen petitions that Copaxone’s complexity and structure preclude a determination of active ingredient sameness for generic glatiramer.

Glatiramer can be adequately characterized, FDA said, and an ANDA applicant can demonstrate active ingredient sameness by showing equivalence between the generic and Copaxone on four key criteria.

Complexity alone does not preclude a finding of active ingredient sameness and ANDA approval, FDA said.

“A demonstration that these criteria are satisfied will ensure that the molecular identity and diversity of glatiramer acetate is equivalent to that of the active ingredient in Copaxone and will establish active ingredient sameness between a generic glatiramer acetate and Copaxone,” FDA said in a citizen petition response signed by Center for Drug Evaluation and Research Director Janet Woodcock.

Glatopa Gets Nod While Others Wait

On April 16, FDA approved Glatopa as an AB-rated generic to Copaxone. However, the timing of generic launch is unclear due to ongoing litigation over Teva’s manufacturing process patent for the drug ([A#14150416003]).

While FDA determined that the Sandoz/Momenta generic met the four criteria for demonstrating sameness to Copaxone, it’s unclear where other glatiramer ANDAs stand vis a vis these requirements.

For example, Mylan NV has an application partnered with Natco Pharma Ltd. that is undergoing FDA review. Synthon BV also has a pending ANDA.

In a statement, Mylan VP-Global Communications Nina Devlin said the company has “responded to all FDA requests to date in terms of our ANDA for our generic Copaxone, and we remain fully confident that we are well positioned to receive approval for our application.”

The Sandoz ANDA approval “demonstrates that the FDA is moving forward with approvals of substitutable generic versions of this product,” Devlin said, adding that the company is confident its ANDA meets the criteria outlined by FDA.

Synthon said its product “satisfies detailed and state-of-art analytical characterization testing to show sameness to Copaxone with respect to primary structure, higher order structure, physicochemical properties and biological activity.”

Four Criteria For Sameness

Teva has waged an extensive regulatory, scientific and legal battle to fend off generics of the 20 mg/mL once-daily Copaxone formulation while it gained approval of, and converted patients to, a 40 mg formulation that is dosed three times a week Also see "Copaxone Reduces Its Dosing Schedule, But Can It Shrink The Competition?" - Pink Sheet, 31 January, 2014..

Starting in September 2008, Teva filed a total of eight citizen petitions requesting that FDA not approve Copaxone generics until certain conditions had been met.

In its most recent petition, filed April 1, Teva sought to require that glatiramer ANDAs include information demonstrating that the generic contains the identical active ingredient as Copaxone, not merely an active ingredient that is similar or highly similar.

Teva asserted that Copaxone’s structural complexity and other unique characteristics render it impossible at this time for an ANDA applicant to demonstrate that its proposed generic product has the same active ingredient as Copaxone.

Teva also sought to require results of nonclinical and clinical studies demonstrating that the proposed generic’s immunogenicity risks are no greater than those for Copaxone, and a demonstration of bioequivalence through comparative clinical investigations in relapsing-remitting MS patients.

However, in an April 16 response, FDA denied all of Teva’s requests for relief.

As a threshold issue, the agency concluded that “complexity alone does not preclude a finding of active ingredient sameness between a generic glatiramer acetate injection and Copaxone.”

Rather, an ANDA applicant can demonstrate active ingredient sameness by showing equivalence based on four criteria, the agency said (see box).

Copaxone Equivalence Criteria

Fundamental reaction scheme
Physicochemical properties including composition
Structural signatures for polymerization and depolymerization
Results in a biological assay

Notably, the criteria are not identical to those governing sameness determinations for generics of another complex molecule, Sanofi’s Lovenox (enoxaparin) Also see "FDA Approves Momenta/Sandoz' Lovenox Generic Without Need For Clinical Studies" - Pink Sheet, 26 July, 2010..

Teva argued that the standards FDA issued in 2010 governing enoxaparin could not be used to demonstrate sameness for other complex products, such as Copaxone Also see "The Lovenox Benchmark: Copaxone "Far More Complex," Teva Argues In Anti-Generic Petition" - Pink Sheet, 3 January, 2011..

Although there is some overlap between the Lovenox and Copaxone criteria, FDA said, the latter “have been uniquely designed … to take into account the nature of the active ingredient glatiramer acetate.”

The first three Copaxone criteria “provide successively refined evidence of active ingredient sameness, while the fourth criterion provides confirmation of active ingredient sameness established by the initial three criteria,” FDA said.

“These four criteria take into account the inherent molecular diversity associated with glatiramer acetate and, taken together, are designed to provide overlapping and confirmatory evidence of active ingredient sameness,” the agency said.

The agency places these criteria in the context of a reference listed drug for which batch-to-batch variability was observed.

“We do not recommend that an ANDA applicant show that based on these four criteria, any given batch of the product described in its ANDA is identical to any single batch of the RLD. This is consistent with the nature of Copaxone, which has inherent batch-to-batch variability,” FDA said.

“Rather, we evaluate active ingredient sameness by considering the level of variability in the RLD compared to that of the proposed generic product,” FDA said.

“A sameness evaluation of these criteria will be based upon qualitative and/or quantitative comparisons of a generic glatiramer acetate injection to multiple batches of Copaxone, taking into consideration the batch-to-batch variability, sampling of Copaxone, and analytical test variability.”

Relevance To Other Products

FDA’s petition suggests that the Sandoz/Momenta generic met these criteria but does not divulge much in the way of specifics about the product.

For example, in its description of the third criterion, FDA said it anticipates that each ANDA applicant “will develop its own set of structural signatures for its generic product and will compare these signatures to the RLD. Each applicant will also provide information to support the validity of its proposed structural signatures and the corresponding methods.”

A footnote states that Sandoz “developed such structural signatures and established equivalence of such signatures between its glatiramer acetate injection and the RLD in connection with the ANDA that we are approving today.”

FDA conducted its own analytical testing of different products to confirm the robustness of the sameness criteria.

The agency tested multiple batches of Copaxone, the Sandoz generic, glatiramer acetate-like products marketed outside the U.S. (including samples of Natco products marketed in India and Ukraine), and negative controls.

“This method is sufficiently sensitive such that the batch-to-batch variations of Copaxone can be detected,” FDA said. “Based on appropriate statistical analysis of the results, the glatiramer acetate-like products marketed outside of the U.S. and negative controls can be clearly distinguished from Copaxone batches. However, when applying the same testing, no significant differences were observed between the proposed generic glatiramer acetate injection under consideration by FDA and Copaxone.”

Bioequivalence And Immunogenicity

FDA also rejected Teva’s argument that ANDA applicants should be required to submit in vivo evidence of bioequivalence due to Copaxone’s colloidal characteristics.

“A biowaiver is appropriate for a glatiramer acetate injection that is a parenteral solution and qualitatively and quantitatively the same in terms of active and inactive ingredients as Copaxone because bioequivalence is considered self-evident,” FDA said.

“The assertions made by Teva regarding Copaxone’s colloidal properties are not consistent with its characterization as a solution because solutions can have colloidal properties.”

The agency also concluded that comparative clinical testing on immunogenicity is not needed.

“Provided that active ingredient sameness and the other ANDA approval requirements are met, the generic product will be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in its labeling and thus can be substituted for the RLD,” FDA said.

“We expect that any glatiramer acetate injection that meets the requirements for ANDA approval will not be associated with greater immunogenicity risks than Copaxone.”

Teva’s Gene Expression Data Unconvincing

FDA’s response includes a section dedicated to gene expression data.

It is understood that FDA requested gene expression data from glatiramer ANDA applicants. Momenta, Mylan and Synthon have said they submitted such data.

In its petitions, Teva compared the effects of Copaxone and other glatiramer products (none of which were approved in the U.S.) on gene expression in mouse splenocytes or human monocytes. Teva asserted the studies identified differences between Copaxone and the comparators that warranted further investigation ([A#14140703006]).

However, FDA found fault with Teva’s various study designs and analyses, concluding that the experiments and data “did not provide useful information relevant to the issue of the approvability of an ANDA referencing Copaxone.”

In a footnote, FDA said that in general, microarray-derived gene expression data alone could be used as part of the total evidence presented in support of active ingredient sameness but could not serve as standalone evidence.

However, such data are “not necessary in this instance because the active ingredient sameness criteria described above are sufficient in that the criteria are robust and provide overlapping and confirmatory evidence of active ingredient sameness.”

Copaxone Generics: FDA Approval Standards Defy Teva’s Argument On Complexity

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