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In re Genentech, Inc., Herceptin (Trastuzumab) Marketing and Sales Practices Litigation

United States District Court, N.D. Oklahoma

March 20, 2019




         Before the Court is the Amended Motion for Summary Judgment Based on Federal Preemption (Doc. 201) filed by defendant Genentech, Inc. (“Genentech”). Plaintiffs oppose the motion.

         I. Introduction

         Genentech manufactures, markets and distributes Herceptin® (hereafter, “Herceptin”), a biologic drug used to treat breast cancer. Plaintiffs are cancer treatment providers who have purchased Herceptin for treatment of their patients. Plaintiffs do not challenge the efficacy or safety of the drug, but contend that Herceptin's labeling is misleading because, although the Herceptin label states that each vial contains 440 mg of Herceptin at a concentration of 21 mg/mL, not every vial contains that amount or more. They assert California state law claims for breach of express and implied warranties and unjust enrichment, and they seek actual damages, costs and attorneys' fees. Doc. 45 at 13-20. Genentech, in its Motion for Summary Judgment, contends that Plaintiffs' claims are preempted by federal law.

         II. Background

         Federal law gives the Food and Drug Administration (“FDA”) the authority and responsibility to regulate prescription drugs. See 21 U.S.C. § 301 et seq. The FDA regulates virtually every aspect of the manufacturing, distribution, evaluation and labeling of drugs marketed and sold in the United States. See Bruesewitz v. Wyeth LLC, 562 U.S. 223, 237 (2011) (noting pervasive regulation of vaccine licensing). The FDA drug approval process is “onerous and lengthy.” Mutual Pharm. Co., Inc. v. Bartlett, 570 U.S. 472, 476 (2013).

         Biologics[1] such as Herceptin are similarly regulated. See 21 U.S. § 321(g)(1). Before a biologic product can be distributed, the FDA must approve the sponsor's biologic license application (“BLA”). 21 U.S.C. § 355(b), 42 U.S.C. §262(a). The BLA contains “specifications” for the product, which establish criteria for determining whether each lot of the biologic satisfactorily conforms to the drug product, as approved by the FDA. 21 C.F.R. § 211.165(a). It also includes data from studies showing that the product meets prescribed requirements for safety, purity and potency; a full description of manufacturing methods; data establishing product stability; samples of the product, labeling, and containers; and summaries of product test results. Id., §§ 601.2(a), 600.3(kk). Manufacturers of biologic products are required to test each lot of the product for, inter alia, potency, safety, purity and sterility. Id., §§ 610.10, 610.12-14. If a lot does not meet the specifications, it cannot be distributed to the public and must be rejected. Id., § 211.165(f).

         The FDA will approve a BLA only if it determines that the manufacturer's biological product and facilities comply with federal regulations. Id., § 601.4. Essentially, a biologics license reflects the FDA's determination that the product is safe, pure and effective, and that the manufacturer's facilities and processes are adequate to meet these high standards. Id., § 601.2(d).

         The biologic product's accompanying labeling must also conform to federal law. 21 U.S.C. §§ 331(a), 352; 21 C.F.R. § 601.2(a). The FDA will approve a BLA only if it finds that the drug is “safe for use” under the conditions “prescribed, recommended, or suggested in the proposed labeling, ” and it will approve the labeling only if it is not “false or misleading in any particular.” 21 U.S.C. § 355(d)(1) & (7).

         Additionally, applicants must notify the FDA about “each change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling established in the approved license application(s).” 21 C.F.R. § 601.12(a). Prior FDA approval is usually required for labeling changes, particularly if the proposed change would affect the information that must appear in the Highlights of Prescribing Information section of the physician package insert. Id., § 601.12(f)(1) (citing § 201.57(a)).

         III. Statement of Undisputed Material Facts

         Twenty to thirty percent of breast cancers are known to have amplification of a growth factor receptor gene known as HER2, and women whose breast cancers have a high level of expression of this gene have a shortened survival rate. Doc. 201-2, Def. Ex. 2 at 7. Herceptin- known generically as trastuzumab-is a prescription drug that helps stop the cancer's growth by targeting HER2 protein. Doc. 201-1, Def. Ex. 1 at 2. Trastuzumad's effect in fighting this aggressive form of cancer has been described as “dramatic, ” and trials have shown that addition of the drug to chemotherapy “resulted in a remarkable 50% reduction in disease recurrence compared with patients receiving chemotherapy alone.” Doc. 201-3, Def. Ex. 3 at 3, Korkaya, H., et al., HER2 and Breast Cancer Stem Cells: More than Meets the Eye, 73 Cancer Research 3489-93 (June 15, 2013)).

         Herceptin is a biologic product produced from living organisms-namely, Chinese hamster ovary cells that have been genetically modified to produce trastuzumab, the active ingredient. Doc. 201-5, Def. Ex. 5, Dec. of Dr. David T. Lin, ¶30; Doc. 201-6, Def. Ex. 6, Dec. of Dana L. Swisher, ¶¶ 5-7. Its production begins in large bioreactor tanks with modified cells replicating in a culture medium and producing trastuzumab. Id., Swisher Dec., ¶ 7. Eventually, the protein trastuzumab is harvested from the cells, a process involving several purification steps to remove cell debris and other unwanted elements. Id. The resulting protein solution is referred to as the “drug substance.” Id. The drug substance is tested to ensure the protein concentration is within the FDA-approved range of 25 milligrams per milliliter (mg/mL), plus or minus 1 mg/mL. Id., ¶ 8. If the drug substance concentration is outside the approved range, the batch is rejected. Id. If it is within the approved range, it is frozen for storage and shipping. Id.

         Tanks of frozen Herceptin drug substance are shipped to manufacturing facilities, where they are thawed and tested again to ensure the concentration is still within the FDA-approved range of 25 mg/mL ± 1mg/mL. Id., ¶9. From there, one or more tanks of Herceptin substance may be pooled. Id. Generally, the next step prior to filling is sterile filtration. Id., ¶10. During this step, the drug substance passes through a sterilization-grade filter and on to the fill line. Id. The drug substance is then filtered, sterilized and dispensed into glass vials by filling machines. Id., ¶ 11. The target fill weight for each vial is 17.92 grams, but the FDA-approved acceptable outer range is 17.56 to 18.28 grams, i.e. 17.92 g ± 2%. Id. A range around the target fill weight of 17.92 grams is necessary because the filling equipment is incapable of filling every vial with precisely 17.92 grams. Id.

         The vials of drug substance are lyophilized or freeze-dried, removing most of the water and leaving what is known as the Herceptin “cake, ” comprised of the dry solid protein and some inactive ingredients. Id., ¶12. The FDA-approved specification for protein content of the drug product is 440 mg± 35mg/mL per vial. Id., ¶12. After the vials are filled and sealed, sample vials are submitted to Quality Control, where they undergo final testing prior to release for distribution. Id., ¶13. The sample vials are identified in the Certificate of Analysis (“COA”). Id. The protein content of the vials is tested in accordance with protocol Q12398. Id. ¶¶13, 16.

         Because the precise concentration of the drug substance and the precise fill weight varies from batch to batch, the weight of the Herceptin cake in each vial will also vary in a range around 440 mg. Id., ¶ 14. When shipped, each vial of Herceptin is accompanied by a vial of sterile water that providers use to dissolve the powder cake-a process known as reconstitution. Id., Doc. 201-1, Ex. 1, Highlights of Prescribing Information.

         The FDA approved the BLA for Herceptin on September 25, 1998. Doc. 201-4, Def Ex. 4. The BLA provides for Herceptin drug substance concentrations within a range of 25 mg/mL ± 1mg/mL and drug product levels within a range of 440 mg ± 35 mg. Id. The FDA also approved Herceptin labeling that claimed 440 mg per vial, recognizing in subsequent correspondence with Genentech that the “expected recovery from each vial is approximately 19 mL or 400 mg.” Doc. 377-1, Def. Ex. 13. Additionally, in 1999, the FDA drafted a letter to providers explicitly referring to the fact that the vials were designed to deliver 400 mg. Doc. 201-5, Def. Ex. 5, Lin Dec, ¶¶47-49 (citing Def. Ex. 13, supra). U.S. Pharmacopeia (“USP”) General Chapter ˂905˃, Uniformity of Dosage Units, provides for an allowable variation of 15 percent from the stated weight. Id., Lin Dec, ¶ 29 and Ex. D thereto, p. 494, Table 2.

         Plaintiffs' own data show that:

• Herceptin drug substance concentrations have always complied with the FDA-approved range of 25 mg/mL ± 1 mg/mL, and
• Herceptin drug product levels always complied with the FDA-approved range of 440 mg± 35 mg.

         Doc. 368, Pls.' SOF 5, 10, 26.

         The term “nominal” in prescription drug labeling refers to a “theoretical” amount, signaling that the actual amount in each vial will vary. Doc. 201-5, Def. Ex. 5, Lin Dec., ¶ 36; Doc 377-2, Def. Ex. 14 at 145:20-146:8.

         The Prescribing Information[2] states that Herceptin is shipped in multi-dose vials “nominally containing 440 mg Herceptin as a lyophilized, sterile powder.” Doc. 201-1, Def. Ex. 1, Highlights of Prescribing Information at 1. Similarly, the carton for each vial states that “the nominal content of each HERCEPTIN vial is 440 mg Trastuzumab.” Id., Doc. 201-7, Def. Ex. 7. This description in labeling is consistent with the FDA-approved specification of 440 mg ± 35 mg and the variability permitted under FDA regulations. Id.

         The Herceptin carton and vial labels state that reconstitution will “yield a multiple-dose solution containing approximately 21 mg/mL Trastuzumab.” 201-7, Def. Ex. 7; Doc. 201-8, Def. Ex. 8. The concentration is “approximately” 21 mg/ml because the actual concentration depends on the amount of Herceptin in each vial, which varies, and the amount of sterile water a provider injects during reconstitution, which also varies. Doc. 201-5, Def. Ex. 5, Lin Dec., ¶¶ 38-40, 43. Additionally, each vial of Herceptin contains a residual and variable amount of moisture-up to three percent-that may be lost over time due to absorption by the stopper on the vial. Id., ¶ 33.

         For each year from 2000 through 2008, a majority of the Herceptin batches released in the United States contained at least 440 mg of trastuzumab. Doc. 368 at 16, Pls. SOF 10. In 2000, 2001, and 2006, more than 82 percent of Herceptin batches contained at least 440 mg of trastuzumab, and in 1998 and 2005, 100 percent of batches met or exceeded the label claim. Id. Pls.' SOF 11. However, the proportion of batches containing at least 440 mg of trastuzumab dropped below 50 percent by 2009 and has not exceeded 50 percent since then. Id., Pls. SOF 10. Only one of the 125 batches tested in the three-year period of 2012-2014 contained at least 440 mg of trastuzumab per vial, and in 2012 and 2014, none of the 89 Herceptin batches tested contained 440 mg or more. Id., Pls. SOF 10-11, 14. Nevertheless, at no time from 1998 to 2017 did any batch contain less than the lower limit of 405 mg of trastuzumab approved by the FDA. Doc. 201-6, Def. Ex. 6, Swisher Dec., ¶14.

         Between the FDA's initial approval of Herceptin on September 25, 1998, and February 3, 2017, the FDA approved more than 10 supplemental applications from Genentech proposing revisions to the Herceptin Prescribing Information without ever directing Genentech to change the description of net weight or concentration. Doc. 201-5, Def. Ex. 5, Lin Dec., ¶ 50. For example, on October 12, 2012, Genentech submitted a prior approval supplement to the FDA requesting approval for the Hillsboro Technical Operations manufacturing facility to manufacture 440 mg vials. Doc. 377-13, Def. Ex. 25. The supplement included data on three qualification batches of Herceptin drug product, and the protein content for all three batches was below 440 mg. Doc. 377-14, Def. Ex. 26. The FDA approved the supplement on February 14, 2013. Doc. 377-15, Def. Ex. 27. On June 6, 2014, the FDA approved a supplement for a manufacturing facility, that also included data on three qualification batches for which the protein content was below 440 mg. Doc. 377-16, Def. Ex. 28.

         In March 2014, the FDA published a Draft Guidance for Industry Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products. Doc. 370-31, Pls. Ex. 31. The Draft Guidance stated that “with respect to allowable excess volume, the sponsor/applicant of drugs in ampules or vials, intended for injection must follow the requirements in 21 CFR 201.51(g).”[3] The Draft Guidance was finalized in June 2015. Doc. 370-34, Pls. Ex. 34.

         On October 30, 2014, after the FDA received complaints from an unidentified oncology pharmacy specialist and other oncology institutions about the inability of end users to withdraw a full 21 mL volume from a vial of Herceptin, FDA and Genentech representatives conducted a teleconference. Doc. 201-9, Def. Ex. 9 at 2. During the teleconference, the FDA asked Genentech to provide a formal written response addressing the FDA's concerns regarding labeling of the Herceptin 440 mg multi-dose vial. Id. at 4.[4] The FDA also proposed that in order to provide further clarity, the Herceptin 440 mg label should be revised to reflect the maximum amount that can be withdrawn from the vial, in accordance with the agency's interpretation of 21 C.F.R. § 201.51(g), as reflected in the 2014 Draft Guidance for Industry: Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products, March 2014. Doc. 201-9, Def. Ex. 9, Resp. to FDA's Comments Regarding Herceptin 440 mg Multi-Dose Vial Fill at October 3, 2014 Teleconference, at pp. 3-4.

         Approximately a month later, in its December 5, 2014, response, Genentech proposed the addition of language stating that recovery of Herceptin may be lower when the 440 mg vial is used as a multi-use vial. Id. at 4-5. The FDA did not reply to Genentech's response until February 3, 2017-more than two years after Genentech submitted proposed labeling changes. Doc. 201-10, Def. Ex. 10. During that time, in April 2015 and March 2016, it approved two unrelated labeling supplements that did not change the way net contents were described. Doc. 201-5, Def. Ex. 5, Lin Decl., ¶¶ 58, 71 n. 68.

         In its February 3, 2017, Advice Letter, the FDA disagreed with Genentech's proposed labeling changes and directed the company to submit a plan to address revision of the labeling from 440 mg per vial to 420 mg per vial on all labeling and to prepare a communication plan to educate healthcare practitioners on the labeling change. Doc. 201-10, Def. Ex. 10.

         Genentech submitted a response to the letter on February 10, 2017. Id., Doc. 201-11, Def. Ex. 11. In its response, Genentech agreed to “update the Herceptin USPI of the previously referred to as the ‘440 mg' strength to the 420 mg strength that reflects the minimally recoverable volume for the Herceptin vial presentation;” to “commit to providing updated carton/container labeling as a Post-Marketing Commitment, ” and to “provide an updated communication plan at the time the revised carton/container are submitted.” Id. The FDA approved the supplemental BLA the same day. Id., Doc. 201-12, Def. Ex. 12.

         If Genentech were required to ensure that every vial contained exactly (or at least) 440 mg of Herceptin, it would have to either change its manufacturing processes-including filling and lyophilization, and possibly the amount of diluent for reconstitution-and seek FDA approval for a protein content specification that deviates from the currently approved range of 440 mg ± 35 mg., or-as Plaintiffs suggest-stop selling vials that fail to meet the approved range. Doc. 201, Def. Ex. 6, Swisher Dec., ¶ 15; Doc 368 at 68-69.

         The manufacture of Herceptin is an aseptic (sterile) processing operation, and substituting steps in an aseptic processing operation is a “major change” requiring FDA approval. Doc. 377, Ex. 17, U.S. BLA Herceptin, GENE-FL0000000527-529, 55521; C.F.R.§ 601.12(b)(2)(vi). Moreover, changing the target fill rate, which is an in-process specification identified in the BLA, also requires prior FDA approval. Doc. 377, Def. Ex. 14, Lin Dep. at 151:1-25; 21 C.F.R. § 601.12(b)(2)(i) (referencing changes in qualitative or quantitative formulation or in the specifications provided in the approved application). See also 21 C.F.R. §211.110(a)(), (b) (referencing “in-process specifications” applicable to drug product “weight variation”); Ex. 22, FDA Guidance for Industry, Changes to an ...

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