Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 1 of 38 Page ID #:1
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`
`
`Todd Benoff (Bar No. 192983)
`Todd.Benoff@alston.com
`ALSTON & BIRD LLP
`333 South Hope Street, 16th Floor
`Los Angeles, CA 90071
`Telephone: (213) 576-1000
`Facsimile:
`(213) 576-1100
`
`Natalie Clayton
`ALSTON & BIRD LLP
`90 Park Ave., 15th Floor
`New York, NY 10016
`Telephone: (214) 922-3400
`Facsimile:
`(214) 922-3899
`(Additional counsel on signature page)
`
`Attorneys for Plaintiff Sandoz Inc.
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`UNITED STATES DISTRICT COURT
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`CENTRAL DISTRICT OF CALIFORNIA
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`WESTERN DIVISION
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`SANDOZ INC.,
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` Plaintiff,
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`vs.
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`AMGEN INC. and
`AMGEN MANUFACTURING
`LIMITED,
`
` Defendants.
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`Case No. ________________
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`COMPLAINT FOR:
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`i. False Advertising (in violation of the
`Lanham Act, Section 43(a), 15 U.S.C. §
`1125 et seq.);
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`ii. False Advertising (in violation of Cal.
`Bus. & Prof. Code §§ 17500 et seq.);
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`iii. Unfair Competition (in violation of Cal.
`Bus. & Prof. Code §§ 17200 et seq.)
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`DEMAND FOR JURY TRIAL
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 2 of 38 Page ID #:2
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`PRELIMINARY STATEMENT
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`1.
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`Plaintiff Sandoz Inc. (“Sandoz” or “Plaintiff”) brings this action for false
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`advertising, by and through its counsel, against Defendants Amgen Inc. and Amgen
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`Manufacturing Limited (collectively, “Amgen” or “Defendants”).
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`2.
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`Sandoz is a pioneer and global leader in providing affordable biosimilar
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`products to patients. In particular, Sandoz has devoted significant resources to develop,
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`manufacture, market and sell a pegfilgrastim prefilled syringe product, sold under the
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`brand name Ziextenzo®, which is used to reduce the incidence of infections in patients
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`with cancer receiving chemotherapy.
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`3.
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`The Food and Drug Administration (“FDA”) approved Sandoz’s
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`Ziextenzo® product as a biosimilar to Amgen’s pegfilgrastim prefilled syringe named
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`Neulasta®, only for Amgen to taint the marketplace shortly after Sandoz launched its
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`product.
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`4.
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`Amgen has engaged in a deliberate and audacious marketing campaign that
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`falsely states that pegfilgrastim prefilled syringe products, which includes Sandoz’s
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`Ziextenzo® product, are less effective and thus, by implication, less safe as compared
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`to Amgen’s pegfilgrastim administered through its on-body device, named Neulasta®
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`Onpro®. Relying on inadequately designed studies—for which Amgen has already
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`been admonished once by the FDA—Amgen has made false and misleading statements
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`to the medical and healthcare communities and public representing that its product is
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`superior in safety and efficacy when it is not.
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`5.
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`Amgen willfully disseminated erroneous scientific conclusions in a bold
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`effort to undermine Sandoz’s ability to provide patients more affordable medicine,
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`competing unfairly to the detriment of Sandoz and others. The data do not support
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`Amgen’s erroneous claims that pegfilgrastim prefilled syringe products, including
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`Sandoz’s Ziextenzo®, are less effective than Neulasta® Onpro®. Amgen’s
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`comparative advertising claims are false and misleading.
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`6.
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`Defendants’ actions constitute false advertising in violation of Section
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 3 of 38 Page ID #:3
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`43(a)(1)(B) of the Lanham Act, 15 U.S.C. § 1125(a)(1)(B); false advertising in violation
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`of California False Advertising Law, Cal. Bus. & Prof. Code § 17500 et seq.; and unfair
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`competition in violation of California Unfair Competition Law, Cal. Bus. & Prof. Code
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`§ 17200. Plaintiff seeks permanent injunctive relief, Plaintiff’s damages, disgorged
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`profits, corrective advertising, recovery of Plaintiff’s costs and reasonable attorneys’
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`fees incurred in connection with this action and such other, different, and additional
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`relief as the Court deems just and proper.
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`JURISDICTION AND VENUE
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`7.
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`This Court has subject matter jurisdiction over this dispute pursuant to 28
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`U.S.C. §§ 1331, 1338 and 15 U.S.C. § 1121(a) because this action arises under the
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`Lanham Act, 15 U.S.C. §§ 1051, et seq.
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`8.
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`This Court has jurisdiction over all state law claims pursuant to 28 U.S.C.
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`§§ 1367 and 1338(b).
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`9.
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`This Court has personal jurisdiction over Defendants because Defendants
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`transact business within the State of California, contract to supply goods or services in
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`the State of California, including but not limited to Neulasta®, have engaged in tortious
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`acts within the State of California, and have engaged in tortious acts outside the State
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`of California causing injury within the State. More specifically, Defendants market,
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`promote, advertise, offer for sale, sell, and/or distribute their products, including
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`Neulasta®, to customers and/or others throughout the United States, including in the
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`Central District of California. Upon information and belief, Defendant Amgen
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`Manufacturing Limited manufactures products, including Neulasta®, for and/or in
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`coordination with Defendant Amgen, and each Defendant serves the market in this
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`District. Defendant Amgen Manufacturing Limited’s involvement with Neulasta® is
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`further evidenced by the fact that it was a plaintiff along with Amgen Inc. in the patent
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`suit brought in federal court in California regarding Sandoz’s biosimilar version of
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`Neulasta®. Defendants have purposefully and voluntarily placed their products,
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`including Neulasta®, into the stream of commerce with the expectation that they will
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 4 of 38 Page ID #:4
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`be purchased by consumers in the Central District of California. Defendant Amgen Inc.
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`also resides in this District, having a principal place of business at One Amgen Center
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`Drive, Thousand Oaks, California 91320. As such, Defendants have established
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`minimum contacts with the forum such that the exercise of jurisdiction over them would
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`not offend traditional notions of fair play and substantial justice.
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`10. Venue is proper in this district under 28 U.S.C. § 1391(b) because Amgen
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`Inc. resides in this District and a substantial part of the events and injury giving rise to
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`Plaintiff’s claims has and continues to occur in this District.
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`THE PARTIES
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`11. Sandoz Inc. is a corporation organized and existing under the laws of the
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`State of Delaware, with its principal place of business at 100 College Road West,
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`Princeton, New Jersey 08540. Sandoz develops, manufactures and sells generic and
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`biosimilar medicines, providing access to high-quality, affordable medicines to millions
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`of patients.
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`12. Amgen Inc. is a corporation organized and existing under the laws of the
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`State of Delaware, with its principal place of business at One Amgen Center Drive,
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`Thousand Oaks, California 91320.
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`13. Amgen Inc. develops, manufactures, markets and sells medicines
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`addressing various therapeutic areas throughout the United States, including in this
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`District.
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`14. Amgen Manufacturing Limited is a corporation organized and existing
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`under the laws of the Territory of Bermuda with its principal place of business at Road
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`31 km 24.6, Juncos, Puerto Rico 00777.
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`15. Amgen Manufacturing Limited, a wholly owned subsidiary of Amgen Inc.,
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`manufactures, markets and sells medicines addressing various therapeutic areas
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`throughout the United States, including in this District.
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`16. Amgen Inc. controls, directs and supervises the activities of Amgen
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`Manufacturing Limited, as well as its employees.
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 5 of 38 Page ID #:5
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`GENERAL FACTUAL ALLEGATIONS
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`A. Biologics and Regulatory Pathway for Biosimilars
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`17. The products at issue in this litigation are biologic products. Biologics,
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`unlike conventional drugs, are isolated from a variety of natural sources: human, animal,
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`or microorganism.
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`18. To market a new biologic product, a company must submit to the FDA a
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`biologics license application (“BLA”).
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`19. The Biologics Price Competition and Innovation Act of 2009 (“BPCIA”),
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`Pub. L. No. 111-148, §§ 7001-7003, 124 Stat. 119, 804-21 (2010) (amending, inter alia,
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`35 U.S.C. § 271 and 42 U.S.C. § 262), created an abbreviated pathway for the approval
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`of biologics that are biosimilar to an FDA-approved reference biologic product.
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`20. A biosimilar is “highly similar to the reference product notwithstanding
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`minor differences in clinically inactive components,” and has “no clinically meaningful
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`differences” from the reference product in terms of “safety, purity, and potency.” 42
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`U.S.C. § 262(i)(2).
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`21. A biosimilar must have the same route of administration, dosage form,
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`strength, mechanism of action, and conditions of use as the approved reference product.
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`42 U.S.C. § 262(k)(2)(A)(i)(II)–(IV).
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`22. Biosimilarity is based on analytical studies; animal studies, including
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`toxicity assessments; and a clinical study or studies, including assessments of
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`immunogenicity and pharmacokinetics or pharmacodynamics. 42 U.S.C. §
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`262(k)(2)(A)(i)(I).
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`23. Biosimilars undergo an extensive regulatory evaluation and approval
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`process by the FDA to prove they match the quality, safety and efficacy of the reference
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`product.
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`24. A company seeking approval of a biosimilar must submit to the FDA an
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`abbreviated BLA (“aBLA”). An aBLA can rely on clinical studies that were performed
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`by the reference biologic product sponsor.
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 6 of 38 Page ID #:6
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`25. An aBLA cannot be filed until four years after the date the reference
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`product was first licensed for approval. 42 U.S.C. § 262(k)(7)(B). Reference products
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`also have twelve years of marketing exclusivity before approval of a biosimilar can be
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`made effective. 42 U.S.C. § 262(k)(7)(A).
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`26. The FDA maintains an online database with information regarding FDA-
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`licensed biological products and biosimilar products approved by the FDA, otherwise
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`known as the “Purple Book.”
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`27. Once FDA licenses a biosimilar product, physicians and patients can be
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`certain of the safety and effectiveness of a biosimilar product as compared to the
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`reference product.
`B.
`Sandoz: A Leader in Biosimilars
`28. Sandoz has proven itself as a pioneer and global leader in developing,
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`manufacturing, marketing and selling biosimilar products.
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`29. Sandoz was the first company to launch a biosimilar product, Zarxio®, in
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`the U.S. and worldwide. Sandoz launched Zarxio®, a filgrastim product, in the U.S. in
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`2015. Zarxio® is biosimilar to Amgen’s reference product Neupogen®.
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`30. Sandoz and Amgen have previously engaged in patent litigation related to
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`Zarxio®, which Sandoz won. This was a major hit for Amgen, and in the wake of its
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`litigation loss, Amgen made clear that it was prepared to compete against Sandoz and
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`retain
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`its market
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`share.
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` See https://www.biopharma-reporter.com/Article/
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`2015/07/31/Amgen-prepped-to-compete-in-US-filgastrim-market-post-Zarxio-launch
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`(last accessed June 15, 2022).
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`31. Notwithstanding fierce competition from Amgen, Sandoz’s Zarxio® was
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`immensely successful, and became the first biosimilar to surpass its reference product
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`in market share.
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`32. Sandoz has devoted significant resources to stay at the forefront of the
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`biosimilar industry and provide patients with safe and effective biologic products.
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`33. Sandoz is committed to bringing biosimilars to more patients around the
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 7 of 38 Page ID #:7
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`world. Sandoz has made a strong investment in manufacturing biosimilars, having end-
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`to-end capabilities to ensure the reliable development, manufacturing and supply of
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`industry-leading, quality biosimilars. Sandoz has a robust pipeline of biosimilar
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`products and, as the first company to bring biosimilars to patients in both the U.S. and
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`worldwide, has a proven track record in delivering biosimilars to patients.
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`34. Sandoz’s biosimilars have provided greater patient access to life-saving
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`medicines, while increasing healthcare savings. Indeed, Sandoz’s biosimilars are
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`generally less expensive than their respective reference products, making affordable
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`medications available to more patients.
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`C. Amgen’s Pegfilgrastim Products: Neulasta® Prefilled Syringe and
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`Neulasta® Onpro®
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`35. Pegfilgrastim is a biologic product, specifically a recombinant human
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`granulocyte colony stimulating factor (“G-CSF”) used to stimulate the production of
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`certain white blood cells called neutrophils.
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`36. Pegfilgrastim is administered to patients to counteract febrile neutropenia
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`(“FN”), a reduction in white blood cells, which is a common and dangerous side effect
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`of chemotherapy drugs used to treat certain forms of cancer. A person with neutropenia
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`is highly vulnerable to life-threatening infection.
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`37.
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`In 2002, Amgen’s BLA for pegfilgrastim administered via subcutaneous
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`injection was approved and launched under the brand name Neulasta®.
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`38. Upon information and belief, the BLA for Neulasta® is owned by Amgen
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`Inc. and exclusively licensed to Amgen Manufacturing Limited.
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`39. Amgen’s pegfilgrastim injection is delivered via a prefilled syringe
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`(“PFS”) (hereinafter, “Neulasta® PFS”).
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`40. Since 2002, Amgen’s Neulasta® product has generated billions in revenue
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`for Amgen. Upon information and belief, to preserve this billion-dollar revenue stream,
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`Amgen implemented various tactics to try to retain its market share and revenue stream
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`in the face of impending biosimilar competition.
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 8 of 38 Page ID #:8
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`41. For example, in 2014, around the time that Amgen’s marketing exclusivity
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`was ending, Amgen received FDA approval for a second presentation of pegfilgrastim:
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`a single-use prefilled syringe of pegfilgrastim co-packaged with an on-body injector.
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`Amgen launched this product nationally in 2015 under the brand name Neulasta®
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`Onpro®. Upon information and belief, Amgen developed, sought approval for, and
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`launched its second presentation of pegfilgrastim because of the development of
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`biosimilar pegfilgrastim products by companies like Sandoz. Indeed, the first aBLA for
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`pegfilgrastim was filed in 2014 and the second in 2015. Thus, upon information and
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`belief, Amgen hoped that a different presentation of pegfilgrastim would stymie
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`competition by the biosimilar pegfilgrastim products.
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`42. While Amgen’s Neulasta® products have different presentations, they
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`have identical indications: to decrease the incidence of infection, as manifested by
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`febrile neutropenia,
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`in patients with non-myeloid malignancies
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`receiving
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`myelosuppressive anti-cancer drugs associated with a clinically significant incidence of
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`febrile neutropenia; and to increase survival in patients acutely exposed to
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`myelosuppressive doses of radiation.
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`43. Amgen’s Neulasta® PFS and Neulasta® Onpro® are marketed and sold
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`nationally, including in this District.
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`44. Upon information and belief, Amgen’s marketing efforts for Neulasta®
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`and Neulasta® Onpro® are conducted, directed and/or supervised from its corporate
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`headquarters in Thousand Oaks, California.
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`D.
`Sandoz’s Pegfilgrastim Biosimilar: Ziextenzo® Prefilled Syringe
`45. With the objective of expanding patient access to high-quality biosimilar
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`medicines at affordable prices, Sandoz spent significant resources researching and
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`developing a pegfilgrastim PFS product biosimilar to Neulasta® PFS.
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`46. Sandoz submitted aBLA No. 761045 to the FDA for pegfilgrastim PFS in
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`2015.
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`47. On May 12, 2016, Defendants filed a patent infringement action against
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 9 of 38 Page ID #:9
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`Sandoz Inc., Sandoz International GmbH, Sandoz GmbH, and Lek Pharmaceuticals d.d.
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`arising out of the submission of Sandoz’s aBLA for pegfilgrastim PFS. (Amgen Inc. et
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`al. v. Sandoz Inc. et al., Case No. 3:16-cv-02581-RS, N.D. California). The District
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`Court for the Northern District of California granted Sandoz’s motion for summary
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`judgment of noninfringement on December 19, 2017 and the U.S. Court of Appeals for
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`the Federal Circuit affirmed that decision on May 8, 2019 (Amgen Inc. et al. v. Sandoz
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`Inc. et al., Appeal No. 2018-1551).
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`48. The FDA subsequently approved Sandoz’s aBLA on November 4, 2019,
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`for the indication of decreasing the incidence of infection, as manifested by febrile
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`neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive
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`anti-cancer drugs associated with a clinically significant incidence of febrile
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`neutropenia. Sandoz launched its pegfilgrastim PFS thereafter, under the brand name
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`Ziextenzo®, throughout the U.S., including in this District.
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`49. Sandoz’s Ziextenzo® product directly competes with Amgen’s
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`pegfilgrastim products, Neulasta® PFS and Neulasta® Onpro®.
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`50. Although Sandoz played by the rules of the biosimilar approval pathway,
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`prevailed in the patent litigation and secured approval of its biosimilar pegfilgrastim
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`PFS, Sandoz has not been able to fully reap the benefit of its labors. Rather, Sandoz’s
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`Ziextenzo® has been subjected to a barrage of false and misleading advertising by
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`Amgen from the early days of its launch through the present, causing harm to Sandoz
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`and its Ziextenzo® product.
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`E. Amgen’s False and Misleading Advertising
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`1.
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`Amgen’s Initial False Advertising Claims Pegfilgrastim PFS Is
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`Less Effective And Thus, By Implication, Less Safe Than
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`Neulasta® Onpro® (2020-2021)
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`51.
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`In the wake of its patent litigation loss against Sandoz, after Sandoz’s
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`Ziextenzo® product launched, in 2020 Amgen willfully and in bad faith engaged in a
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`national advertising campaign that made false and misleading comparisons between its
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 10 of 38 Page ID #:10
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`Neulasta® Onpro® and other pegfilgrastim PFS products, including Ziextenzo®. That
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`campaign was introduced into interstate commerce, appearing on the Neulasta®
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`Onpro® website and in direct communications to the medical and healthcare
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`communities.
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`52. Amgen disseminated the following promotional claims in its commercial
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`advertisements:
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`a) “In a Real-World Study with nearly 11,000 patients Pegfilgrastim PFS resulted
`in a significantly higher risk of FN+ vs Onpro®1”
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`b) “Across all cycles of chemotherapy, the incidence of FN associated with prefilled
`syringe (PFS) was 1.7% (n=455) vs 1.3% (n=126) for Neulasta® Onpro®.1”
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`c) “31%* *p=0.01” (written on large presentation of an upward arrow)
`d) “With PFS, FN incidence increased by 31% vs Onpro®1”.
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`See Exhibit 1 to the Complaint (emphasis in original) [Exhibit 1A is original copy of
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`advertising reviewed by FDA, available at https://www.fda.gov/media/150752/
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`download; Exhibit 1B is enlarged view provided for ease of viewing]. By using bold
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`graphics and dramatically comparative language such as “significantly higher,” Amgen
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`knowingly and intentionally drew a direct comparison between Onpro® and
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`pegfilgrastim PFS products.
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`53. Amgen’s advertising was designed to knowingly and intentionally draw
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`this comparison:
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 11 of 38 Page ID #:11
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`See Exhibit 1.
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`54.
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`In support of these statements, Amgen referenced and relied on “Data on
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`file, Amgen; 2019.” See Exhibit 1 (at reference 1).
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`55.
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`In its advertising, Amgen describes the “data on file” as a “Real-World
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`Study” that was “designed to compare the incidence of FN associated with Neulasta®
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`Onpro® vs Neulasta® PFS among patients receiving myelosuppressive chemotherapy”
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`(hereinafter, the “2019 Amgen Study”). As explained below, this statement is false as
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`Amgen’s study was not designed to support making such a comparison.
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`56. Much later in the advertising after the false comparative claims and in
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`smaller print, Amgen’s advertising specifies two “Real-World Study Limitations,” as
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`follows:
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`“• Retrospective analysis that did not control for additional variables that may
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`influence the incidence of FN
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`• Database was not sufficient to understand root causes for observed lower rate
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`of FN for patients receiving Onpro®.”
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`See Exhibit 1. As further explained below, such a disclaimer is incomplete and
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`misleading.
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`57. Amgen’s statements are not supported by any scientifically rigorous
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`clinical study; rather, the 2019 Amgen Study was a retrospective, observational study
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 12 of 38 Page ID #:12
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`that collected preexisting patient data from databases called MarketScan® Commercial
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`Claims and Encounters/Medicare Supplemental and Coordination of Benefits, which is
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`insufficient to support Amgen’s claims.
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`58. Upon information and belief, for the 2019 Amgen Study, Amgen collected
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`data for patients that had initiated chemotherapy with administration of pegfilgrastim
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`via Neulasta® PFS and Neulasta® Onpro®, categorized that data and made certain
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`conclusions regarding the incidence of febrile neutropenia in the patients. Notably, and
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`contrary to the broad statements in Amgen’s advertising, all patients at issue received
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`the Neulasta® product, and none received a biosimilar pegfilgrastim PFS.
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`59. Upon information and belief, although an abstract discussed similar
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`information to that used in the 2019 Amgen Study (see Exhibit 2), the 2019 Amgen
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`Study has never been the subject of a final manuscript published in a peer-reviewed
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`journal and, therefore, has not been the subject of independent, rigorous scientific
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`review.
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`60. While Amgen’s advertising points to the 2019 Amgen Study as alleged
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`support for its claims that Neulasta® Onpro® is more efficacious than pegfilgrastim
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`PFS, the 2019 Amgen Study does not reliably support the conclusions that Amgen
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`makes in its false and misleading advertising. A non-exhaustive description of the
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`reasons that the 2019 Amgen Study does not reliably support Amgen’s claims is
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`provided herein.
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`61. The 2019 Amgen Study is not a prospective, randomized, well-controlled,
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`well-powered, comparative clinical study that would support the comparative
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`statements made by Amgen in its advertisements.
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`62. A randomized study provides a method of assigning subjects to groups in
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`a manner intended to minimize bias and assure comparability of the groups with respect
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`to factors such as age, gender, severity of disease, duration of disease, and use of other
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`drugs or treatments other than the test drugs, with the intention to keep all factors
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`similarly balanced between
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`the
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`treatment groups except for
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`the
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`treatment
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 13 of 38 Page ID #:13
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`assignment. Randomized studies also assign trial subjects to a treatment using an
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`element of chance to reduce bias.
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`63. A well-controlled clinical study uses the specification of inclusion and
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`exclusion eligibility criteria to provide a formal method of selection of test subjects that
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`provides adequate assurances that subjects have the disease or condition being studied.
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`64. A well-powered clinical study includes pre-specified endpoint criteria
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`applicable to all patients, thus resulting in an appropriate number of subjects to make
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`scientifically valid conclusions.
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`65. Comparative clinical studies include adequate and well-controlled trials
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`designed to establish whether one treatment is superior to another. Accordingly, to
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`make the comparative superiority claims that Amgen made in its advertisements, a
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`head-to-head controlled study between Neulasta® Onpro® and pegfilgrastim PFS
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`products is required to support Amgen’s claims. The 2019 Amgen Study is not such a
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`study, and Amgen’s advertising did not cite any such head-to-head study.
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`66. Further, the 2019 Amgen Study is not an adequately designed
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`observational study that can support Amgen’s comparative advertising claims.
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`67. Amgen’s advertising describes the 2019 Amgen Study as a “real-world”
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`study. “Real-World Evidence” is “clinical evidence regarding the usage and potential
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`benefits or risks of a medical product derived from analysis of [real-world data].” See
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`Real World Evidence, available at https://www.fda.gov/science-research/science-and-
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`research-special-topics/real-world-evidence (last accessed June 3, 2022). Real-world
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`data includes “data relating to patient health status and/or the delivery of health care
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`routinely collected from a variety of sources,” such as electronic health records, claims
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`and billing activities, product and disease registries, patient generated data, etc. See id.
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`Real-world evidence (“RWE”) can be obtained from retrospective or prospective
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`observational studies.
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`68. There are well-established standards to follow when conducting RWE
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`(e.g., Good Research Practices of the International Society for Pharmacoeconomics and
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 14 of 38 Page ID #:14
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`Outcomes Research (ISPOR)), especially where causal inferences are being drawn
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`regarding comparative effectiveness, to avoid bias and the impact of confounding
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`factors. To have robust real-world evidence, the underlying study should, among other
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`things, select the most appropriate observational dataset (e.g., insurance claims data vs.
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`patient self-reports vs. medical records) and algorithm to avoid misclassification. RWE
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`studies should also account for bias by: (1) controlling for patient eligibility, and (2)
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`statistically controlling each comparison group so that it has an identical distribution of
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`measured and unmeasured risk factors (e.g., propensity score weighing - estimates of
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`each patient’s probability of treatment given all measured covariates). Prudent
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`application of statistical analysis techniques is also critical. The 2019 Amgen Study
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`was not designed using any of these requirements and, as a result, the 2019 Amgen
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`Study has numerous, substantive flaws that render Amgen’s conclusions scientifically
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`unreliable and unsupportable.
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`69.
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` First, Amgen did not appropriately identify and select its cohorts.
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`Amgen’s advertisements made comparisons between Neulasta® Onpro® and
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`pegfilgrastim PFS, noting that delivery via “Pegfilgrastim PFS resulted in a
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`significantly higher risk of FN vs Onpro.” See Exhibit 1. But the 2019 Amgen Study
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`failed to ensure that the PFS and Onpro® patient populations were adequately balanced
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`or controlled for potential bias, e.g., comorbidity or risk factors for febrile neutropenia,
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`such as age, chemotherapy regimen and dosing, etc.—all factors which influence the
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`development of febrile neutropenia. By failing to use any objectively defined pre-
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`specified inclusion and/or exclusion criteria to develop two cohorts without selection
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`bias and comparable baseline characteristics that would permit a scientifically valid
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`comparative examination of the products, Amgen ignored clinical factors, including by
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`failing to evaluate the influence of various clinical factors on outcomes through
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`stratification, that would influence both the chance of being administered pegfilgrastim
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`PFS vs. Onpro® and the risk of developing febrile neutropenia. It is well understood
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`that a causal relationship between the administration method and outcome cannot be
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 15 of 38 Page ID #:15
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`inferred without controlling for bias.
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`70. Second,
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`the conclusions
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`in Amgen’s advertising are statistically
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`flawed. Upon information and belief, Amgen determined the febrile neutropenia
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`incidence rates (1.3% for Onpro® and 1.7% for PFS) and a p-value of 0.01 (a value
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`which communicates whether the observed difference is real or due to play-of-chance)
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`by using the total number of pegfilgrastim cycles and not the total number of
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`patients. To determine incidence rates and p-value based on treatment cycles
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`contravenes well-accepted, basic statistical principles as Amgen is not counting
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`independent observations of febrile neutropenia. Rather, by analyzing incidence rates
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`based on treatment cycles, Amgen ignores the correlation of repeated values within one
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`patient and may count a single patient’s incidence of febrile neutropenia more than once
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`in subsequent cycles. Ignoring this correlation data structure is improper as it can
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`artificially reduce the p-value, making the conclusions seem significant when they are
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`not. Amgen erroneously increased the sample size from nearly 11,000 (patients) to
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`approximately 36,000 (pegfilgrastim cycles), making the p-value of 0.01 reported in the
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`advertising false and misleading.
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`71. Third, even if the results Amgen presented were based on the number of
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`patients, the 2019 Amgen Study is still erroneous because it uses a sample size of
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`eligible patients that can detect very small effect sizes of no clinical relevance and can
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`be alternatively explained by biases in the sampling process, making the reported p-
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`value misleading. Again, a causal relationship between the administration method and
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`outcome cannot be inferred without controlling for biases and examining the clinical
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`relevance of the difference observed in light of the sample size.
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`72. Fourth, Amgen’s statements allege superior results from Neulasta®
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`Onpro® versus pegfilgrastim PFS for febrile neutropenia, but the study was not
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`designed to ensure that patients with febrile neutropenia were appropriately identified
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`for inclusion in the analysis. Upon information and belief, Amgen used an unvalidated
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`algorithm with unknown performance characteristics (e.g., sensitivity, positive
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`Case 2:22-cv-05326 Document 1 Filed 08/01/22 Page 16 of 38 Page ID #:16
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`predictive value) leading to the potential for misclassification of patients at the onset of
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`the study. As a result, the extent of febrile neutropenia could be overestimated or
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`underestimated and, thus, cannot support Amgen’s advertising claims of superiority.
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`73.
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`In fact, after seeing the abstract reflecting similar data to the 2019 Amgen
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`Study and its obvious flaws, Sandoz employees and professional colleagues conducted
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`an evaluation of the same patient population from the MarketScan databases r