Case 1:19-cv-13432-NLH-AMD Document 62 Filed 08/20/19 Page 1 of 42 PageID: 903
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`KETTERER BROWNE & ANDERSON
`BY: DEREK BRASLOW, ESQUIRE
`
`ATTORNEY I.D. NO: DB4681
`
`11130 Sunrise Valley Drive, Ste 140
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`Reston, VA 20190
`
`T: (410) 885-6215
`
`LITTLEPAGE BOOTH LECKMAN
`BY: T. MATTHEW LECKMAN, ESQUIRE
`Pro Hac Vice
`1912 W. Main St.
`Houston, TX 77098
`T: (713) 529-8000
`
`Attorneys for Plaintiff
`
`
`
`
`
`
`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`
`
`
`Case No. 1:19-cv-13432-NLH-AMD
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`AMENDED COMPLAINT
`
`
`(Document Electronically Filed)
`
`KIMBERLY GREMO,
`
`
`Plaintiff,
`
`
`
`vs.
`
`
`BAYER CORPORATION;
`BAYER HEALTHCARE LLC;
`BAYER HEALTHCARE
`PHARMACEUTICALS, INC.; GE
`HEALTHCARE, INC.;
`GENERAL ELECTRIC COMPANY;
`MALLINCKRODT, INC.;
`MALLINCKRODT LLC; GUERBERT LLC;
`LIEBEL-FLARSHEIM COMPANY LLC;
`AMERISOURCE BERGEN CORPORATION;
`and AMERISOURCE BERGEN DRUG
`CORPORATION,
`
`
`Defendants.
`
`
`
`

`

`Case 1:19-cv-13432-NLH-AMD Document 62 Filed 08/20/19 Page 2 of 42 PageID: 904
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`Plaintiff Kimberly Gremo, by and through undersigned counsel, brings this action against
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`Defendants Bayer Corporation, Bayer HealthCare LLC, Bayer HealthCare Pharmaceuticals, Inc.
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`(collectively “Bayer”), GE Healthcare, Inc., General Electric Company (collectively “GE”),
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`Mallinckrodt, Inc., Mallinckrodt LLC (collectively “Mallinckrodt”), Guerbert LLC (“Guerbert”),
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`Liebel-Flarsheim Company LLC (Liebel-Flarsheim), Amerisource Bergen Corporation, and
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`Amerisource Bergen Drug Corporation (collectively “Amerisource”), alleging the following upon
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`information and belief (including investigation made by and through Plaintiff’s counsel), except
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`those allegations that pertain to Plaintiff, which are based on personal knowledge.
`
`I.
`
`INTRODUCTION
`
`1.
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`This action arises out of the Plaintiff Kimberly Gremo’s exposure to Defendants’
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`Magnetic Resonance Imaging (“MRI”) prescription linear gadolinium-based contrast agents
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`(“GBCAs”) in the State of New Jersey. Plaintiff’s injuries and damages are a direct and proximate
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`result of the negligent, reckless, willful, and wanton conduct of Defendants, and/or their corporate
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`predecessors, in connection with the research, development, design, testing, licensing,
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`manufacturing, distribution, supply, labeling, marketing and sale of their linear GBCAs.
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`2.
`
`Plaintiff brings suit under the New Jersey Products Liability Act, N.J.S.A. 2A:58C-
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`1, et seq. (“NJPLA”), the New Jersey Punitive Damages Act, N.J.S.A. 2A:15-5.9, et seq., and the
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`common law of the State of New Jersey, to recover damages and other relief as described, for the
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`injuries Plaintiff sustained as set forth herein.
`
`II.
`
`PARTIES
`
`3.
`
`Plaintiff is an adult and citizen of Marmora, New Jersey.
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`The Bayer Defendants
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`4.
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`Defendant Bayer Corporation is, and at all relevant times has been, engaged in the
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`
`2
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`research, development, design, testing, licensing, manufacturing, distribution, supply, labeling,
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`marketing, and sale of its prescription linear GBCA, Magnevist (gadopentetate), to which Plaintiff
`
`was exposed, as well as its other GBCAs: Eovist and Gadavist.
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`5.
`
`Defendant Bayer Corporation is, and at all relevant times has been, engaged in the
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`distribution, supply, marketing, and sale of its GBCAs in the State of New Jersey.
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`6.
`
`Defendant Bayer Corporation is a for-profit corporation that is incorporated under
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`the laws of Indiana.
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`7.
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`Defendant Bayer Corporation contends that its principal place of business is in New
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`Jersey.
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`8.
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`Defendant Bayer Corporation is registered with the New Jersey Division of
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`Revenue and Enterprise Services to conduct business, and does conduct business, in the State of
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`New Jersey.
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`9.
`
`Defendant Bayer Corporation may be served with process by serving its registered
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`agent, Corporation Trust Company, located at 820 Bear Tavern Rd., West Trenton, NJ 08628.
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`10.
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`Defendant Bayer HealthCare LLC is, and at all relevant times has been, engaged in
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`the research, development, design, testing, licensing, manufacturing, distribution, supply, labeling,
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`marketing, and sale of its prescription linear GBCA, Magnevist, to which Plaintiff was exposed,
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`as well as its other GBCAs: Eovist (linear) and Gadavist (macrocyclic).
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`11. Defendant Bayer HealthCare LLC is, and at all relevant times has been, engaged in
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`the distribution, supply, marketing, and sale of its GBCAs in the State of New Jersey.
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`12. Defendant Bayer HealthCare LLC is a for-profit limited liability company
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`organized under the laws of Delaware.
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`13. Defendant Bayer HealthCare LLC contends that its principal place of business is in
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`
`
`3
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`New Jersey.
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`14. Defendant Bayer HealthCare LLC is registered with the New Jersey Division of
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`Revenue and Enterprise Services to conduct business, and does conduct business, in the State of
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`New Jersey.
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`15. Defendant Bayer HealthCare LLC may be served with process by serving its
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`registered agent, Princeton South Corporate Center, located at 100 Charles Ewing Blvd., Suite
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`160, Ewing Township, NJ 08628.
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`16.
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`Defendant Bayer HealthCare Pharmaceuticals, Inc. is, and at all relevant times has
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`been, engaged in the research, development, design, testing, licensing, manufacturing, distribution,
`
`supply, labeling, marketing, and sale of its prescription linear GBCA, Magnevist, to which
`
`Plaintiff was exposed, as well as its other GBCAs: Eovist (linear) and Gadavist (macrocyclic).
`
`17.
`
`Defendant Bayer HealthCare Pharmaceuticals, Inc. is, and at all relevant times has
`
`been, engaged in the distribution, supply, marketing, and sale of its GBCAs in the State of New
`
`Jersey.
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`18.
`
`Defendant Bayer HealthCare Pharmaceuticals, Inc. is a for-profit corporation that
`
`is incorporated under the laws of Delaware.
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`19.
`
`Defendant Bayer HealthCare Pharmaceuticals, Inc. contends that its principal place
`
`of business is in New Jersey.
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`20.
`
`Defendant Bayer HealthCare Pharmaceuticals, Inc. is registered with the New
`
`Jersey Division of Revenue and Enterprise Services to conduct business, and does conduct
`
`business, in the State of New Jersey.
`
`21.
`
`Defendant Bayer HealthCare Pharmaceuticals, Inc. may be served with process by
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`serving its registered agent, Corporation Service Company, located at 2711 Centerville Road,
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`
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`4
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`

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`Wilmington, DE 19803.
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`The GE Defendants
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`22.
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`Defendant GE Healthcare, Inc. is, and at all relevant times has been, engaged in the
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`research, development, design, testing, licensing, manufacturing, distribution, supply, labeling,
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`marketing, and sale of its prescription linear GBCA Omniscan (gadodiamide), to which Plaintiff
`
`was exposed.
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`23.
`
`Defendant GE Healthcare, Inc. is, and at all relevant times has been, engaged in the
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`distribution, supply, marketing, and sale of Omniscan in the State of New Jersey.
`
`24.
`
`Defendant GE Healthcare, Inc. is a for-profit corporation that is incorporated under
`
`the laws of Delaware.
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`25.
`
`Defendant GE Healthcare, Inc. contends that its principal place of business is in
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`Massachusetts.
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`26.
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`Defendant GE Healthcare, Inc., is registered with the New Jersey Division of
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`Revenue and Enterprise Services to conduct business, and does conduct business, in the State of
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`New Jersey.
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`27.
`
`Defendant GE Healthcare, Inc. may be served with process by serving its registered
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`agent, Corporation Trust Company, located at 820 Bear Tavern Road, West Trenton, NJ 08628.
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`28.
`
`Defendant General Electric Company is, and at all relevant times has been, engaged
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`in the research, development, design, testing, licensing, manufacturing, distribution, supply,
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`labeling, marketing, and sale of its prescription linear GBCA, Omniscan, to which Plaintiff was
`
`exposed.
`
`29.
`
`Defendant General Electric Company is, and at all relevant times has been, engaged
`
`in the distribution, supply, marketing, and sale of Omniscan in the State of New Jersey.
`
`
`
`5
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`30.
`
`Defendant General Electric Company is a for-profit corporation that is incorporated
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`under the laws of New York.
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`31.
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`Defendant General Electric Company contends that its principal place of business
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`is in Massachusetts.
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`32.
`
`Defendant General Electric Company is registered with the New Jersey Division of
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`Revenue and Enterprise Services to conduct business, and does conduct business, in the State of
`
`New Jersey.
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`33.
`
`Defendant General Electric Company may be served with process by serving its
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`registered agent, Corporation Trust Company, located at 820 Bear Tavern Road, West Trenton, NJ
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`08628.
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`The Guerbet and Mallinckrodt Defendants
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`34.
`
`Defendants Guerbert LLC, Mallinckrodt Inc., Mallinckrodt LLC, and Liebel-
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`Flarsheim Company LLC are, and at all relevant times have been, engaged in the research,
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`development, design, testing, licensing, manufacturing, distribution, supply, labeling, marketing,
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`and sale of their prescription linear GBCA, OptiMARK (gadoversetamide), to which Plaintiff was
`
`exposed.
`
`35.
`
`Defendant Mallinckrodt, Inc. is, and at all relevant times has been, engaged in the
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`distribution, supply, marketing, and sale of OptiMARK in the State of New Jersey.
`
`36.
`
`Defendant Mallinckrodt, Inc. is a for-profit corporation that is incorporated under
`
`the laws of Delaware.
`
`37.
`
`Defendant Mallinckrodt, Inc. contends that its principal place of business is in
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`Missouri.
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`38.
`
`Defendant Mallinckrodt, Inc. is registered with the New Jersey Division of Revenue
`
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`
`6
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`and Enterprise Services to conduct business, and does conduct business, in the State of New Jersey.
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`39.
`
`Defendant Mallinckrodt, Inc. may be served with process by serving its registered
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`agent, The Corporation Trust Company, located at 820 Bear Tavern Road, West Trenton, NJ
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`08628.
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`40.
`
`Defendant Mallinckrodt LLC is, and at all relevant times has been, engaged in the
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`research, development, design, testing, licensing, manufacturing, distribution, supply, labeling,
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`marketing, and sale of OptiMARK, to which Plaintiff was exposed.
`
`41.
`
`Defendant Mallinckrodt LLC is, and at all relevant times has been, engaged in the
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`distribution, supply, marketing, and sale of OptiMARK in the State of New Jersey.
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`42.
`
`Defendant Mallinckrodt LLC is a for-profit limited liability company that is
`
`incorporated under the laws of Delaware.
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`43.
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`Defendant Mallinckrodt LLC contends that its principal place of business is in
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`Missouri.
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`44.
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`Defendant Mallinckrodt LLC is registered with the New Jersey Division of
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`Revenue and Enterprise Services to conduct business, and does conduct business, in the State of
`
`New Jersey.
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`45.
`
`Defendant Mallinckrodt LLC may be served with process by serving its registered
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`agent, Corporation Trust Company, located at 820 Bear Tavern Road, West Trenton, NJ 08628.
`
`46.
`
`Upon information and belief, Defendant Mallinckrodt Inc. developed, invented,
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`manufactured, tested, marketed, advertised, and sold linear GBCA named OptiMARK before it
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`sold its contrast media portfolio, including OptiMARK, to Guerbert LLC in or around 2015.
`
`47.
`
`Defendant Guerbert LLC is, and at all relevant times has been, engaged in the
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`research, development, design, testing, licensing, manufacturing, distribution, supply, labeling,
`
`
`
`7
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`

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`marketing, and sale of its prescription linear GBCA, OptiMARK, to which Plaintiff was exposed,
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`as well as its prescription macrocyclic GBCA, Dotarem.
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`48.
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`Defendant Guerbert LLC manufactured, tested, marketed, advertised and sold the
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`OptiMARK before it removed OptiMARK from United States market in or around 2018.
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`49.
`
`Defendant Guerbert LLC is, and at all relevant times has been, engaged in the
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`distribution, supply, marketing, and sale of OptiMARK in the State of New Jersey.
`
`50.
`
`Defendant Guerbert LLC is a for-profit limited liability company that is
`
`incorporated under the laws of Delaware.
`
`51.
`
`Defendant Guerbert LLC contends that its principal place of business is in New
`
`Jersey.
`
`52.
`
`Defendant Guerbert LLC is registered with the New Jersey Division of Revenue
`
`and Enterprise Services to conduct business, and does conduct business, in the State of New Jersey.
`
`53.
`
`Defendant Guerbert LLC may be served with process by serving its registered
`
`agent, The Corporate Trust Company, located at 820 Bear Tavern Road, West Trenton, NJ 08540.
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`54.
`
`OptiMARK was originally approved by the Food and Drug Administration
`
`(“FDA”) in 1996. The original label stated that OptiMARK was distributed and manufactured by
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`Mallinckrodt Inc.
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`55.
`
`On or around August 2016, OptiMARK’s product label indicated that it was
`
`manufactured and distributed by Defendant Liebel-Flarsheim Company LLC.
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`56.
`
`Defendant Liebel-Flarsheim Company LLC is, and at all relevant times has been,
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`engaged in the research, development, design, testing, licensing, manufacturing, distribution,
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`supply, labeling, marketing, and sale of its prescription linear GBCA, OptiMARK, to which
`
`Plaintiff was exposed.
`
`
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`8
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`57.
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`Defendant Liebel-Flarsheim Company LLC is, and at all relevant times has been,
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`engaged in the distribution, supply, marketing, and sale of OptiMARK in the State of New Jersey.
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`58.
`
`Defendant Liebel-Flarsheim Company LLC is a for-profit limited liability company
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`that is incorporated under the laws of Delaware.
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`59.
`
`Defendant Liebel-Flarsheim Company LLC contends that its principal place of
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`business is in Missouri.
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`60.
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`Defendant Liebel-Flarsheim Company LLC is registered with the New Jersey
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`Division of Revenue and Enterprise Services to conduct business, and does conduct business, in
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`the State of New Jersey.
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`61.
`
`Defendant Liebel-Flarsheim Company LLC may be served with process at 1034
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`South Brentwood Blvd., Richmond Heights, MO 63117.
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`The Amerisource Defendants
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`62.
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`Defendant Amerisource Bergen Corporation is, and at all relevant times has been,
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`engaged in the research, development, design, testing, licensing, manufacturing, distribution,
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`supply, labeling, marketing, and sale of the prescription linear GBCA, OptiMARK, to which
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`Plaintiff was exposed.
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`63.
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`Defendant Amerisource Bergen Corporation is, and at all relevant times has been,
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`engaged in the distribution, supply, marketing, and sale of OptiMARK in the State of New Jersey.
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`64.
`
`Defendant Amerisource Bergen Corporation is a for-profit corporation that is
`
`incorporated under the laws of Delaware.
`
`65.
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`Defendant Amerisource Bergen Corporation contends that its principal place of
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`business is in Pennsylvania.
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`66.
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`Defendant Amerisource Bergen Corporation may be served with process by serving
`
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`9
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`its registered agent, The Corporation Trust Company, located at Corporation Trust Center, 1209
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`Orange Street, Wilmington, DE 19801.
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`67.
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`Defendant Amerisource Bergen Drug Corporation is, and at all relevant times has
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`been, engaged in the research, development, design, testing, licensing, manufacturing, distribution,
`
`supply, labeling, marketing, and sale of the prescription linear GBCA, OptiMARK, to which
`
`Plaintiff was exposed.
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`68.
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`Defendant Amerisource Bergen Drug Corporation is, and at all relevant times has
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`been, engaged in the distribution, supply, marketing, and sale of OptiMARK in the State of New
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`Jersey.
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`69.
`
`Defendant Amerisource Bergen Drug Corporation is a for-profit corporation that is
`
`incorporated under the laws of Delaware.
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`70.
`
`Defendant Amerisource Bergen Drug Corporation contends that its principal place
`
`of business is in Pennsylvania.
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`71.
`
`Defendant Amerisource Bergen Drug Corporation is registered with the New Jersey
`
`Division of Revenue and Enterprise Services to conduct business, and does conduct business, in
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`the State of New Jersey.
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`72.
`
`Defendant Amerisource Bergen Drug Corporation may be served with process by
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`serving its registered agent, The Corporation Trust Company located at 820 Bear Tavern Road.,
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`West Trenton, NJ 08628.
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`III.
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`JURISDICTION AND VENUE
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`73.
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`On April 24, 2019, Plaintiff commenced this action in the Superior Court of New
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`Jersey, Law Division, Atlantic County, by way of Complaint and Demand for Jury Trial.
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`74.
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`On June 5, 2019, Defendants removed this action to this Court by way of a Notice
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`of Removal.
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`10
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`75.
`
`Given that Plaintiff and the Bayer Defendants both reside in New Jersey, diversity
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`jurisdiction is lacking.
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`76.
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`As set forth in Plaintiff’s currently pending motion for remand, there are no grounds
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`that support a federal court’s exercise of subject-matter jurisdiction over the instant matter.
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`77.
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`The New Jersey state court where this action was originally commenced has
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`personal jurisdiction over all Defendants because Plaintiff was exposed to, injured and damaged
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`by Defendants’ GBCAs in New Jersey.
`
`78.
`
`The New Jersey state court where this action was originally commenced has
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`personal jurisdiction over Defendants Bayer HealthCare Pharmaceuticals, Inc., Bayer HealthCare
`
`LLC, Bayer Corporation, and Guerbert LLC, because they are citizens of the State of New Jersey.
`
`79.
`
`The New Jersey state court where this action was originally commenced has
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`personal jurisdiction over all Defendants because they supplied, distributed, shipped, and delivered
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`their GBCAs to healthcare providers throughout the United States, including, upon information
`
`and belief, to Plaintiff’s healthcare providers in the State of New Jersey.
`
`80.
`
`The New Jersey state court where this action was originally commenced has
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`personal jurisdiction over all Defendants because Defendants have engaged in continuous,
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`systematic, and substantial business activities in the State of New Jersey including but not limited
`
`to the marketing and sale of their GBCAs throughout the State of New Jersey.
`
`81.
`
`Venue is proper in Atlantic County, where this action was originally commenced,
`
`pursuant to New Jersey Rule 4:3-2 as Plaintiff was exposed to, injured and damaged by
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`Defendants’ GBCAs in Atlantic County.
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`82.
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`Venue is proper in Atlantic County, where this action was originally commenced,
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`pursuant to New Jersey Rule 4:3-2, in that Defendants regularly conduct substantial business in
`
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`11
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`Atlantic County, New Jersey, including but not limited to the marketing and sale of their GBCAs.
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`
`
`83.
`
`84.
`
`IV. NATURE OF ACTION
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`Gadolinium (Gd) is a rare earth metal.
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`Gadolinium-based contrast agents (“GBCAs”) are chemical compounds that are
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`introduced into the body prior to an MRI procedure in order to enhance the imaging.
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`85.
`
`During various MRI procedures from 2007 to 2016, Plaintiff was exposed to three
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`linear GBCAs: Magnevist (Bayer), Omniscan (GE), and OptiMARK (Mallinckrodt, Guerbert, and
`
`Amerisource).
`
`86.
`
`87.
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`At the time of said exposure, Plaintiff had normal kidney function.
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`As a result of Plaintiff’s exposure to Defendants’ linear GBCAs, gadolinium from
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`Defendants’ linear GBCAs de-chelated and was retained and deposited in her body, directly and
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`proximately causing the injuries set forth herein.
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`88.
`
`At the time of Plaintiff’s exposure to Defendants’ linear GBCAs, the product
`
`labeling for each product was identical in all relevant respects, and each Defendant’s linear GBCA
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`product labeling failed to adequately warn that, inter alia: (1) linear products are less stable or less
`
`safe than their macrocyclic counterparts, and therefore, more prone to de-chelation and retention;
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`(2) all patients, irrespective of kidney functioning, are at risk for gadolinium retention from
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`exposure to linear GBCAs; or (3) gadolinium retention can result not only in NSF but also in NSF-
`
`like injuries on a spectrum leading up to NSF, as characterized by the injuries set forth herein and
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`often referred to as “gadolinium deposition disease” or “gadolinium toxicity” generally.
`
`89.
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`Plaintiff’s development of the injuries set forth herein has caused her pain and
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`suffering and mental anguish, and she brings products claims under the NJPLA and sounding in
`
`
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`12
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`breach of express warranty, seeking compensatory and punitive damages and demanding a trial by
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`jury.
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`V.
`
`FACTUAL BACKGROUND
`
`
`Gadolinium and GBCAs
`
`90.
`
`Gadolinium (Gd) is a chemical element. It sits in the lanthanide metal series of the
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`periodic table and carries atomic number 64 and a relative atomic mass of 157 u.
`
`91.
`
`In its natural state, gadolinium exists only in oxidized form as Gd3+, which is a
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`cation (an ion with more protons than electrons and hence a positive charge).
`
`92.
`
`The gadolinium atom contains seven unpaired electrons in its 4f orbit, which is the
`
`highest possible number of unpaired electron spins that an atom can contain.
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`93.
`
`These unpaired electrons are what makes gadolinium highly paramagnetic, and
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`consequently, uniquely effective for use in Magnetic Resonance Imaging (MRI or MR imaging).
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`94. MR imaging is a medical diagnostic procedure that employs radiofrequency (RF)
`
`waves and a strong magnetic field to temporarily realign protons found in body tissue being
`
`targeted in the particular imaging.
`
`95.
`
`Once RF is applied, the protons in the body’s tissue produce signals captured by a
`
`receiver and are generated into a “picture” of the target area by the MRI machine.
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`96.
`
`Prior to the 1980s, magnetic resonance MRI was ordinarily performed in the
`
`clinical setting without the use of contrast agents.
`
`97.
`
`Eventually, research revealed that introducing a contrast agent into a patient prior
`
`to MRI might safely alter the magnetic properties of target tissues and serve to enhance the
`
`diagnostic imaging.
`
`98.
`
`Today, Gadolinium-based Contrast Agents (GBCAs) are the most widely used
`
`
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`13
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`contrast agents in MR imaging.
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`99.
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`GBCAs shorten what are called the T1 and T2 “relaxation” times of the target
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`tissue, with the net result of higher intensity MR signaling and a clearer MR picture. Gadolinium
`
`has the strongest relaxation rate of all the paramagnetic elements.
`
`100. But gadolinium is toxic. It does not occur naturally in the body, and it is well
`
`accepted in the medical and scientific community that “free” gadolinium is toxic in biological
`
`systems.
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`101. Because gadolinium cannot be safely introduced into the body by itself, GBCAs
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`instead are comprised of “chelated” gadolinium—i.e., Gd3+ that is complexed (or “bound”) by a
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`ligand.
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`102.
`
`“Chelate” is Latin for “claw,” and a simple understanding of the nature of chelated
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`gadolinium is that the ligand serves as a claw holding onto the gadolinium as it passes through the
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`body.
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`103. Thus, the gadolinium in a GBCA is intended to remain chelated as it passes through
`
`and eventually is eliminated from the body, mainly by the kidneys, after the MRI.
`
`104. There are currently nine (9) GBCAs that have been approved by the Food and Drug
`
`Administration (FDA) for use in the United States, and they fall into one of two categories based
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`on the nature of their chelation: linear or macrocyclic.
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`105. Linear chelates are elongated ligand structures that wrap around the Gd3+ ion, like
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`a coil around a cylinder. In contrast, macrocyclic chelates are cage-like structures that trap the
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`Gd3+ ion more securely in a center cavity.
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`106. Because of the structure of GBCAs, there is a risk of “de-chelation,” a process
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`whereby gadolinium can become unbound or freed from its chelate. De-chelation is due in part to
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`the fact that other substances in the body will “compete” with gadolinium for its chelate, including
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`zinc, copper, and iron. In fact, the bond in a GBCA can become very weak and separate very
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`easily in low pH conditions, such as those found in many compartments of the human body
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`including extracellular fluid spaces.
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`107. Once de-chelated, the freed, highly reactive cation Gd3+ will immediately—within
`
`seconds—bind to another substance in the body, and there are a variety of substances in the human
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`body that are available to, and known to bind with, de-chelated Gd3+, including proteins,
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`phosphates and other compounds.
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`108.
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`In short, when de-chelated, gadolinium from GBCAs will bind with, deposit, and
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`remain in the cells and tissue of various organs in the body.
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`109. Because of their structure, macrocyclic GBCAs are more stable and less prone to
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`de-chelation—and hence deposition—in the body. Indeed, laboratory (in vitro) studies assessing
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`the stability of various GBCAs in human blood have demonstrated that, over time, greater
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`percentages of gadolinium are released from linear agents as compared to the macrocyclic agents.
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`Tweedle MF, Eaton SM, Eckelman WC, et al., Comparative chemical structure and
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`pharmacokinetics of MRI contrast agents. Invest. Radiol. 1988, 23 (suppl. 1):S236-S239; see also
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`Frenzel T, Lengsfeld P, Schimer H, et al., Stability of gadolinium-based magnetic resonance
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`imaging contrast agents in serum at 37 degrees C. Invest. Radiol. 2008, 43:817-828.
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`110. The kidneys play a central role in the clearance of GBCAs from the body, so
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`patients with compromised kidney function are at risk for slower or reduced clearance of GBCAs,
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`which in turn increases the risk of de-chelation and retention of free gadolinium in the body.
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`Nephrogenic Systemic Fibrosis (NSF)
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`111. As direct consequence of the skyrocketing use of GBCAs in MRIs in the 1980s and
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`1990s, by the early 2000s, the medical and scientific community began to take note of a never-
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`before-seen disease that was arising in patients with compromised renal function who had been
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`exposed to GBCAs.
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`112.
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`In 2000, Cowper et al. described a new scleroderma-like cutaneous disorder that
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`first presented in 15 dialysis patients. (Cowper et al. 2000). Gross diagnostic symptoms included
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`persistent skin induration, which is an increase in tissue fibrosis elements marked by loss of
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`elasticity and pliability that are commonly associated with inflammation, all presenting mainly in
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`the extremities and trunk with facial sparing. NSF was initially believed to be confined to the skin
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`and dubbed nephrogenic fibrosing dermopathy (NFD). In some patients, however, there is clinical
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`involvement of other tissues (lung, skeletal muscles, heart diaphragm, esophagus, etc.), and the
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`disease was eventually named nephrogenic systemic fibrosis (NSF). NSF evolves abruptly (days
`
`to weeks), with conditions that include skin discoloration and thickening, joint contracture, muscle
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`weakness, and generalized pain (Cowper et al. 2000).
`
`113.
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`In 2006, Grobner first proposed that GBCAs triggered the development of NSF in
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`dialysis patients with underlying metabolic acidosis (Grobner 2006). Prior to this report, only
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`severe or end-stage kidney disease had been associated with NSF.
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`114.
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`In 2007, High et al. reported their results of examining skin and soft tissues from
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`NSF patients who had documented NSF and were exposed to GBCAs. The investigators found
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`detectable gadolinium in 4 of the 13 tissue specimens from 7 patients with documented NSF who
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`were exposed to GBCAs.
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`115.
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`In 2008, Broome et al. showed a strong association between GBCA exposure and
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`NSF, summarizing all known NSF case reports and determining that the vast majority were
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`associated with three GBCAs: 157 cases with Omniscan; 8 with Magnevist; and 3 OptiMARK.
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`116. NSF was uncovered and understood only by the attentive clinical observation and
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`work of dermatologists, nephrologists, and other scientists, who connected the administration of
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`linear GBCAs to this rapidly progressive, debilitating and often fatal condition.
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`117. There were over 500 cases of NSF reported, and it was estimated there were well
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`over a thousand non-reported cases.
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`118. Eventually, the emergence of NSF prompted the Food & Drug Administration
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`(FDA) to require GBCA manufacturers, including all Defendants herein, to strengthen the class
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`product labeling for GBCAs to include a “black box” warning, which first went into the labeling
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`for each of the products at issue in 2007:
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`WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)
`
`See full prescribing information for complete boxed warning.
`
`
`Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among
`patients with impaired elimination of the drugs. Avoid use of GBCAs in these
`patients unless the diagnostic information is essential and not available with
`non-contrasted MRI or other modalities. NSF may result in fatal or
`debilitating fibrosis affecting the skin, muscle and internal organs.
`
` Do not administer Optimark to patients with:
`o chronic, severe kidney disease (GFR < 30 mL/min/1.73m), or
`o acute kidney injury.
`
` •
`
`
`
`
` •
`
` Screen patients for acute kidney injury and other conditions that may reduce
`renal function. For patients at risk for chronically reduced renal function (e.g.
`age > 60 years, hypertension, or diabetes), estimate the glomerular filtration
`rate (GFR) through laboratory testing.
`
`
`OptiMARK Prescribing Information, Revised 8/2016, available at www.guerbet.com, as
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`last accessed on August 19, 2016.
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`119. Because of the black box warning and the medical community’s awareness of the
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`clear connection between GBCAs and NSF in renally impaired patients, the incidence of NSF has
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`all but disappeared, as healthcare practitioners have universally changed MRI prescription habits.
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`120. The association between NSF and kidney disease is attributed to the delay in
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`elimination caused by slow glomerular filtration rates and other impaired renal functions such as
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`those caused by acute kidney disease (Rogosnitzky and Branch 2016). NSF is classified as a multi-
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`organ fibrosing disorder that occurs in both genders and all ethnic groups and has been observed
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`in patients of all ages although the majority of cases occur in adults between 30 and 60 years old.
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`(Cowper et al. 2000, Kanda et al., 2016, Idee et al. 2009).
`
`121.
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`It is undisputed that GBCAs cause NSF, and renal insufficiency is simply a catalyst
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`(Leyba and Wagner 2018). More than 98% of NSF cases occurred in patients who had undergone
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`studies with the linear GBCAs Omniscan, OptiMARK, or Magnevist. (Lenkinski 2017).
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`122.
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`It is now settled in the medical community that GBCAs are a cause of NSF.
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`Authoritative and reliable medical literature has reported that the relative risk for development of
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`the disease in renally impaired patients exposed to GBCAs might be as high 41 (a 4,000%
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`increased risk over baseline) compared to baseline. See Wagner, B., et al. Pathophysiology of
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`gadolinium-associated systemic fibrosis, Am. J. Physiol. Renal Physiol., 311(1): p. F1-F11 (2016).
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`123. NSF is debilitating physically and cognitively and can also be lethal. (Broome
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`2008). Early clinical manifestations of NSF include pain, swelling, skin erythema, pruritus (sever
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`itching of the skin), transient alopecia (hair loss), gastrointestinal symptoms of nausea, vomiting,
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`diarrhea and abdominal pain, as well as dizziness, mental confusion or “fog” (Broome 2008,
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`Parillo at al. 2018).
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`Gadolinium Retention and Adverse Events Irrespective of Kidney Function
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`124. NSF is the end-stage of a broader condition that runs on a c