Health Law Daily Court upholds FDA decision not to transition Copaxone from drug to biological product under PHSA
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Thursday, January 7, 2021

Court upholds FDA decision not to transition Copaxone from drug to biological product under PHSA

By Robert Margolis, J.D.

FDA reasonably interpreted "protein" as requiring "specific, defined sequence" of amino acids, which Teva’s Copaxone product lacks.

The FDA reasonably concluded that Teva Pharmaceuticals, Inc.’s glatiramer acetate product Copaxone is a drug regulated under the Food, Drug, and Cosmetics Act (FDC Act), rather than a biological product regulated under the Public Health Service Act (PHSA), a federal district court in the District of Columbia has held. The court granted summary judgment for the FDA, and generic makers of glatiramer acetate products Sandoz Inc. and Mylan Pharmaceuticals, Inc., who had intervened in the lawsuit brought by Teva to review the agency’s determination (Teva Pharmaceuticals USA, Inc. v. FDA, December 31, 2020, Howell, B.).

Claims. Teva, along with Sandoz and Mylan manufacture therapeutic products using glatiramer acetate to treat multiple sclerosis. Close to 25 years ago, the FDA approved Teva’s product, Copaxone, as a drug under the FDC Act. More recently, the FDA approved generic glatiramer acetate products, including those manufactured by Sandoz and Mylan. Teva subsequently sued the FDA, seeking an order requiring the FDA to regulate Copaxone as a "biological product" under the PHSA, rather than as a "drug" under the FDCA. Teva contends that the Biologics Price Competition and Innovation Act of 2009 (BPCIA), mandates the change, as it added "proteins" and therapeutic products "analogous" to proteins to the definition of "biological product," and required the FDA to transition qualifying drugs to biological product status by March 23, 2020. Sandoz and Mylan intervened as defendants to oppose Teva’s claims, as the change Teva requested would impact their approvals. The parties cross-moved for summary judgment.

Drugs, biologics. Approvals of new "drugs" and "biologics" are governed by different statutes—FDC Act section 505 governs drug approval, while PHSA section 351 governs approval of biologics. "A biologic is a type of drug derived from natural, biological sources such as animals or microorganisms," in contrast to "traditional drugs, which are typically synthesized from chemicals." Sandoz Inc. v. Amgen Inc. (Sandoz), 137 S. Ct. 1664, 1669–70 (2017). After passage of the BPCIA, the FDA developed regulations to interpret "protein" and "chemically synthesized polypeptide" in the amended definition of "biological product" in the BPCIA, and to determine which products would be transitioned from "drug" to "biological product" status. Teva’s lawsuit was prompted by the FDA’s application of the regulations to Teva’s Copaxone product.

In an August 2011 internal memorandum signed by the Directors of FDA’s Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research (2011 Memorandum), the FDA defined "protein" as "any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size" and "chemically synthesized polypeptide" as "any alpha amino acid polymer is that is (a) made entirely by chemical synthesis; and (b) less than 100 amino acids in size."

Glatiramer acetate. As set forth in the 2011 Memorandum, glatiramer acetate is a chemically synthesized "mixture of peptide copolymers containing four specific amino acids in a defined molar ratio." Immediately prior to the BPCIA transition deadline of March 23, 2020, the FDA issued an internal decision memorandum concluding the Copaxone is not a biological product, therefore it would not be transitioned. It reasoned that glatiramer acetate is not a protein "because it does not have a specific, defined sequence." Teva sought review of this decision under the Administrative Review Act.

Reasonable interpretation. The court concluded that the FDA’s interpretation of the term "protein" in PHSA section 351’s definition of "biological product" is reasonable. After rejecting Teva’s argument that deference to the agency’s rulemaking is not warranted because the rule was adopted in a procedurally deficient manner, the court addressed Teva’s challenge to the agency’s definition of "protein requiring a "specific, defined sequence" of amino acids. After first finding that "protein" is ambiguous with respect to the "specific, defined sequence" requirement, such that it is neither compelled nor foreclosed by PHSA section 351, the court had to determine if the FDA’s interpretation was a reasonable construction of the statutory language. Because requiring proteins have a "specific, defined sequence" "falls within the range of scientifically accepted meanings of ‘protein,’" the court upheld the interpretation. Teva had argued that the definition improperly excludes chemically synthesized proteins, but after exhaustively reviewing the record of scientific literature, the court found otherwise. In fact, the Final rule holds that both natural and synthetic proteins must have a specific, defined amino acid sequence, the court pointed out.

Finally, the court held that the FDA’s application of the Final rule in its internal decision memorandum to conclude that Copaxone is not a protein, because it does not meet the "specific, defined sequence" requirement was neither arbitrary nor capricious. Copaxone is not made through a predictable process, but rather through "reaction chemistry," which generates recurring but not identical results across batches. As such, the FDA’s decision that it lacks the requisite "specific, defined sequence" was reasonable.

The case is No. 3:20-cv-00808-BAH.

Attorneys: Andrew Kim (Goodwin Procter LLP) for Teva Pharmaceuticals USA, Inc. and Teva Pharmaceutical Industries Ltd. Kathryn A. Schmidt, U.S. Department of Justice, U.S. Food Drug Administration.

Companies: Teva Pharmaceuticals USA, Inc.

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