Nelson v. Biogen Idec, Inc. et al

MOTION for Summary Judgment

D.N.J.May 15, 2017

Kevin H. Marino John D. Tortorella MARINO, TORTORELLA & BOYLE, P.C. 437 Southern Boulevard Chatham, New Jersey 07928-1488 Telephone: (973) 824-9300 Fax: (973) 824-8425 e-mail: kmarino@khmarino.com OF COUNSEL: Joseph G. Blute (admitted pro hac vice) Yalonda T. Howze (admitted pro hac vice) MINTZ, LEVIN, COHN, FERRIS, GLOVSKY AND POPEO, P.C. One Financial Center Boston, Massachusetts 02111 Tel: (617) 542-6000 Fax: (617) 542-2241 e-mail: jgblute@mintz.com Attorneys for Defendants Biogen Inc. & Elan Pharmaceuticals, LLC UNITED STATES DISTRICT COURT DISTRICT OF NEW JERSEY ANDREW NELSON, Plaintiff, v. BIOGEN INC. AND ELAN PHARMACEUTICALS, LLC, Defendants. Hon. John M. Vazquez, U.S.D.J. No. 2:12-cv-7317-JMV-MF DEFENDANTS’ NOTICE OF MOTION FOR SUMMARY JUDGMENT ORAL ARGUMENT REQUESTED TO: David R. Buchanan Sindhu S. Daniel SEEGER WEISS LLP 550 Broad Street, Suite 920 Newark, New Jersey 07102 Edward F. Blizzard (admitted pro hac vice) Michael Clinton (admitted pro hac vice) BLIZZARD & NABERS, LLP 440 Louisiana Street, Suite 1710 Houston, Texas 77002 PLEASE TAKE NOTICE that at a time and date to be determined by the Court, Defendants Biogen Inc. and Elan Pharmaceuticals, LLC (collectively, “Defendants”), through their attorneys Marino, Tortorella & Boyle, P.C. (Kevin H. Marino, appearing), will move before the Honorable John Michael Vazquez, U.S.D.J., United States District Court for the District of New Jersey, Martin Luther King Building and U.S. Courthouse, 50 Walnut Street, Newark, New Case 2:12-cv-07317-JMV-MF Document 154 Filed 05/15/17 Page 1 of 2 PageID: 2122 2 Jersey, for entry of an Order, pursuant to Fed. R. Civ. P. 56, granting summary judgment in favor of Defendants on Plaintiff’s claim with prejudice. PLEASE TAKE FURTHER NOTICE that, in support of their motion, Defendants will rely on the Memorandum of Law and the Certification of Kevin H. Marino submitted herewith. A proposed form of Order is also submitted herewith. PLEASE TAKE FURTHER NOTICE that Defendants request oral argument. Dated: May 15, 2017 Respectfully submitted, _______________________________ Kevin H. Marino kmarino@khmarino.com John D. Tortorella jtortorella@khmarino.com MARINO, TORTORELLA & BOYLE, P.C. 437 Southern Boulevard Chatham, NJ 07928 Tel: (973) 824-9300 Fax: (973) 824-8425 Joseph G. Blute (admitted pro hac vice) jblute@mintz.com Yalonda T. Howze (admitted pro hac vice) ythowze@mintz.com MINTZ, LEVIN, COHN, FERRIS, GLOVSKY & POPEO, PC One Financial Center Boston, MA 02111 Tel: (617) 542-6000 Fax: (617) 542-2241 Attorneys for Defendants Case 2:12-cv-07317-JMV-MF Document 154 Filed 05/15/17 Page 2 of 2 PageID: 2123 UNITED STATES DISTRICT COURT DISTRICT OF NEW JERSEY ANDREW NELSON, Plaintiff, v. BIOGEN INC. AND ELAN PHARMACEUTICALS, LLC, Defendants. Hon. John M. Vazquez, U.S.D.J. No. 2:12-cv-7317-JMV-MF MEMORANDUM OF LAW IN SUPPORT OF DEFENDANTS’ JOINT MOTION FOR SUMMARY JUDGMENT Kevin H. Marino John D. Tortorella MARINO, TORTORELLA & BOYLE, P.C. 437 Southern Boulevard Chatham, New Jersey 07928-1488 Telephone: (973) 824-9300 Fax: (973) 824-8425 e-mail: kmarino@khmarino.com OF COUNSEL: Joseph G. Blute (admitted pro hac vice) Yalonda T. Howze (admitted pro hac vice) MINTZ, LEVIN, COHN, FERRIS, GLOVSKY AND POPEO, P.C. One Financial Center Boston, Massachusetts 02111 Tel: (617) 542-6000 Fax: (617) 542-2241 e-mail: jgblute@mintz.com Attorneys for Defendants Biogen Inc. & Elan Pharmaceuticals, LLC Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 1 of 49 PageID: 2124 i TABLE OF CONTENTS Page I. INTRODUCTION ...............................................................................................................1 II. STATEMENT OF UNDISPUTED FACTS ........................................................................3 A. Andrew Nelson and Multiple Sclerosis ...................................................................3 B. Tysabri (Natalizumab) .............................................................................................4 1. PML is a Known Risk of Tysabri ................................................................5 2. FDA Required a Black Box PML Warning and the TOUCH Prescribing Program.....................................................................................6 C. Defendants’ Pharmacovigilance Efforts Led to the Discovery of Three PML Risk Factors that Resulted in Amendments to Tysabri’s PML Warnings ..................................................................................................................9 1. In November 2009, While Mr. Nelson was Prescribed Tysabri, FDA Approved a Label Update to Include the Duration of Treatment as a PML Risk Factor ...............................................................10 2. In July 2010, While Mr. Nelson was Prescribed Tysabri, FDA Approved a Label Update to Include Prior Treatment with an Immunosuppressant Drug as a PML Risk Factor ......................................11 3. Biogen Researched and Developed an Assay to Test for the Presence of Anti-JCV Antibodies and Concluded that a Positive Assay Result is a Marker of Increased PML Risk .....................................12 4. In September 2010, FDA Rejected Biogen’s Proposal to Change Tysabri’s Label to Reference Anti-JCV Antibody Testing .......................14 5. In November 2010, FDA Also Rejected Biogen’s Proposal to Make the Anti-JCV Antibody Assay Available to Tysabri Prescribers..................................................................................................16 6. After the Two Clinical Trials and the Submission of Additional Data, FDA Approved an Amendment to Tysabri’s Label Concerning the Significance of Anti-JCV Antibodies in January 2012............................................................................................................17 D. Plaintiff’s Complaint..............................................................................................17 III. ARGUMENT.....................................................................................................................18 A. Choice of Law........................................................................................................18 B. Summary Judgment Standard ................................................................................18 C. Defendants are Entitled to Summary Judgment Because—as Three Courts Have Decided—Tysabri’s Warnings Concerning the PML Risk with Tysabri Treatment are Adequate as a Matter of Law ............................................19 Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 2 of 49 PageID: 2125 ii 1. Tysabri’s FDA-Approved PML Warnings are Presumed Adequate .........19 2. Tysabri’s PML Warnings Informed Plaintiff’s Treating Neurologists of the Precise Risk That is the Basis of Plaintiff’s Failure to Warn Claim ...............................................................................22 D. Defendants Are Entitled to Summary Judgment Because Without Competent Expert Testimony From a Neurologist on the Alleged Inadequacy of the FDA-Approved Label, Plaintiff Cannot Prove the Label was Inadequate.......................................................................................................23 1. Plaintiff’s Expert Does Not Opine About the Adequacy of Tysabri’s Label ..........................................................................................23 2. Plaintiff’s Expert is Not Qualified to Opine About the Adequacy of the Tysabri Label .......................................................................................27 E. Plaintiff Cannot Prove Proximate Cause Because Plaintiff Cannot Meet His Burden of Proving that His Neurologists Would Not Have Prescribed the Drug Had the PML Warnings Been Different .................................................28 F. Defendants are Entitled to Summary Judgment on Claims Regarding Anti- JCV Antibodies Because They are Preempted by Federal Law, as Three Courts Have Held on the Identical FDA Record ...................................................31 1. Plaintiff’s Claims are Preempted Because Defendants Could Not Have Warned About JCV Antibodies and Could Not Have Made an Assay Available Without FDA Approval .............................................31 2. Plaintiff’s Failure to Warn Claims Regarding Anti-JCV Antibodies are Preempted Because There is “Clear Evidence” That FDA Would Not Have Approved Any Such Labeling Changes Before 2012............................................................................................................35 G. Elan Was Not the License-Holder for Tysabri and Had No Legal Right to Initiate a Labeling Change or To Seek FDA Approval For Such A Change; The Failure To Warn Claims Against Elan Are Also Preempted on That Ground ...................................................................................................................39 IV. CONCLUSION..................................................................................................................41 Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 3 of 49 PageID: 2126 iii TABLE OF AUTHORITIES Page(s) Cases Alston v. Caraco Pharm. Inc., 670 F. Supp. 2d 279 (S.D.N.Y. 2009)......................................................................................30 Appleby v. Glaxo Wellcome, Inc., No. 04-cv-0062, 2005 U.S. Dist. LEXIS 32875 (D.N.J. Dec. 13, 2005)...........................25, 29 Baker v. App. Pharms. LLP, No. 09-05725, 2012 U.S. Dist. LEXIS 117970 (D.N.J. Aug. 21, 2012) .................................29 Banner v. Hoffman-La Roche Inc., 891 A.2d 1229 (N.J. App. Div. 2006)......................................................................................24 Brazil v. Janssen Research and Develop. LLC, No. 4:15-cv-0204-HLM, 2016 U.S. Dist. LEXIS 93528 (N.D. Ga, July 11, 2016) ........................................................................................................................................40 Celotex Corp. v. Catrett, 477 U.S. 317 (1986).................................................................................................................18 Cerveny v. Aventis, No. 2:14-cv-00545, 2016 U.S. Dist. LEXIS 34182 (D. Utah March 16, 2016) ......................35 Christison v. Biogen Idec Inc. and Elan Pharm., LLC, No. 2:11-cv-01140-DN-DBP, 2016 U.S. Dist. LEXIS 110273 (D. Utah Aug. 5, 2016) ............................................................................................................................ passim Cooper v. Bristol-Myers Squibb Co., No. 07-cv-885, 2013 U.S. Dist. LEXIS 1768 (D.N.J. Jan. 4, 2013)........................................30 Dobbs v. Wyeth Pharm., 797 F. Supp. 2d 1264 (W.D. Okla. 2011) ................................................................................35 Feldman v. Lederle Lab., 625 A.2d 1066 (N.J. 1993).......................................................................................................34 Gaynor v. Merck Sharp & Dohme Corp., No. 12-1492, 2014 U.S. Dist. LEXIS 82003 (D.N.J. June 17, 2014)......................................23 Gentile v. Biogen Idec Inc. and Elan Pharm., LLC, No. 1181 CV 03500, 2016 Mass. Super. LEXIS 238 (Mass. Sup. Ct. July 25, 2016) ................................................................................................................................ passim Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 4 of 49 PageID: 2127 iv Glynn v. Merck Sharp & Dohme Corp. (In re Fosamax Prods. Liab. Litig.), 951 F. Supp. 2d 695 (D.N.J. 2013) ..........................................................................................35 Grobelny v. Baxter Healthcare Corp., 341 F. App’x 803 (3d Cir. 2009) .............................................................................................19 Grobelny v. Baxter Healthcare Corp., No. 05-cv-4645, 2008 U.S. Dist. LEXIS 41115 (D.N.J. May 23, 2008).................................24 In re: Accutane Litig., In re: Accutane Litig., No. 271 (MCL), 2015 N.J. Super. Unpub. LEXIS 1216, (N.J. Super. Ct. April 2, 2015). ..........................................................................................20, 23 In re: Byetta Cases, No. JCCP 4574, (Ca. Sup. Ct. Nov. 13, 2015).........................................................................39 In re Celexa and Lexapro Mktg. and Sales Practices Litig., 779 F.3d 34 (1st Cir. 2015)..........................................................................................32, 33, 34 In re Fosamax, MDL No. 2243, 2014 U.S. Dist. LEXIS 42253 (D.N.J. March 26, 2014) ..............................39 In re Fosamax Alendronate Sodium Prods. Liab. Litig. Nos. 14-1900 et al., 2017 U.S. App. LEXIS 5075 (3rd Cir. Mar. 22, 2017)...........................35 In re Fosamax Prods. Liab. Litig., No. 3:08-cv-00008, 2012 U.S. Dist. LEXIS 5817 (D.N.J. Jan. 17, 2012)...............................40 In re: Incretin-based Therapies Prods. Liab. Litig., 142 F. Supp. 3d 1108 (S.D. Cal. 2015)..............................................................................35, 39 Jones v. Synthes USA Sales, LLC, No. 08-cv-2060, 2010 U.S. Dist. LEXIS 85744 (D.N.J. Aug. 19, 2010) ................................24 Kaleta v. Abbott Labs., Inc., 87 F. Supp. 3d 916 (S.D. Ill. 2015)..........................................................................6, 33, 35, 39 Kaucher v. Cnty. of Bucks, 455 F.3d 418 (3d Cir. 2006).....................................................................................................18 McElroy v. Eli Lilly & Co., 495 F. App’x. 166 (2d Cir. 2012) ............................................................................................30 Misouria v. Eli Lilly & Co., 394 F. App’x 825 (2d Cir. 2010) .............................................................................................30 Mutual Ins. Co. v. Bartlett, 133 S. Ct. 2466 (2013).................................................................................................31, 32, 34 Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 5 of 49 PageID: 2128 v Niemiera v. Schneider, 555 A.2d 1112 (N.J. 1989).......................................................................................................24 Perez v. Wyeth Labs., Inc., 734 A.2d 1245 (N.J. 1999).......................................................................................................20 PLIVA v. Mensing, 564 U.S. 604, 623-25 (2011). ............................................................................................32, 40 Rheinfrank v. Abbott Labs., Inc., No. 1:13-cv-144, 2015 U.S. Dist. Lexis 104564 (S.D. Ohio Aug. 10, 2015)....................35, 39 Robinson v. McNeil Consumer Healthcare, 615 F.3d 861 (7th Cir. 2010) .............................................................................................35, 39 Rossitto v. Hoffman La-Roche Inc., No. A-1236-13T1, 2016 N.J. Super...................................................................................21, 29 Rowe v. Hoffman La Roche, Inc., 917 A.2d 767 (N.J. 2007).........................................................................................................20 Rowland v. Novartis Pharms. Corp., 34 F. Supp. 3d 556 (W.D. Pa. 2014)........................................................................................25 Seavey v. Globus Med. Inc., No. 11-cv-2240, 2014 U.S. Dist. LEXIS 65985 (D.N.J. Mar. 11, 2014) ..........................20, 24 Seufert v. Merck Sharp & Dohme Corp., No. 13-cv-2169, 2016 U.S. Dist. LEXIS 91837 (S.D. Ca. May 11, 2016)........................34, 39 Spychala v. GD Searle & Co., 705 F. Supp. 1024 (D.N.J. 1988) .............................................................................................26 Strumph v. Schering Corp., 606 A.2d 1140 (N.J. App. Div. 1992) (Skillman, J. dissenting)........................................28, 31 Wyeth v. Levine, 555 U.S. 555 (2009)......................................................................................................... passim Zaza v. Marquess and Nell, Inc., 675 A.2d 620 (N.J. 1996).........................................................................................................19 Statutes N.J.S.A. § 2A:58C-2................................................................................................................19, 24 N.J.S.A. § 2A:58C-4..........................................................................................................19, 20, 34 New Jersey Products Liability Act ................................................................................1, 18, 19, 20 Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 6 of 49 PageID: 2129 vi U.S. Food, Drug, and Cosmetics Act.............................................................................................31 Other Authorities 21 C.F.R. § 201.57(c)(1)............................................................................................................6, 33 21 C.F.R. § 314.3(b) ......................................................................................................................32 21 C.F.R. § 314.70 .........................................................................................................................32 21 C.F.R. § 314.70(c)(6)(iii)..........................................................................................................32 21 C.F.R. § 314.70(c)(6)(iii)(A) (2006).........................................................................................40 44 Fed. Reg. 37434, 37448 (FDA June 26, 1979) ...........................................................................6 44 Fed. Reg. 37434, 37448 (June 26, 1979) ..................................................................................33 Fed. R. Civ. P. 56.................................................................................................................1, 18, 41 Fed. R. Civ. P. 56(a) ......................................................................................................................18 Fed.R.Evid. 407 .............................................................................................................................21 U.S. CONST. art. vi, cl. 2 ................................................................................................................31 Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 7 of 49 PageID: 2130 I. INTRODUCTION Defendants1/ Biogen Inc. (“Biogen”) and Elan Pharmaceuticals, LLC (“Elan”) are entitled to summary judgment in this prescription drug product liability action. Plaintiff’s remaining claim2/ in the Fourth Amended Complaint asserts a single cause of action against Defendants under the New Jersey Product Liability Act (“PLA”) based on an alleged failure to adequately warn about the risk of developing a viral brain infection, “PML,” while being treated with the drug Tysabri.3/ PML is a known and disclosed risk of Tysabri, an FDA-approved biologic drug used in the treatment of multiple sclerosis (“MS”). Throughout the course of Mr. Nelson’s Tysabri treatment, the risk of PML was disclosed in Tysabri’s labeling in a “black box” warning, FDA’s strongest possible warning. The undisputed summary judgment record establishes that there are no genuine issues of material fact and that Biogen and Elan are entitled to summary judgment as a matter of law. Fed. R. Civ. P. 56. Plaintiff has failed to adduce any evidence, including any competent expert opinion testimony, to rebut New Jersey’s statutory presumption that the FDA-approved “black box” PML warning and related warnings in Tysabri’s labeling were adequate. In fact, three courts recently held, on an identical FDA regulatory record, that Tysabri’s PML warnings were adequate as a matter of law. See Christison v. Biogen Idec Inc. & Elan Pharm., LLC, No. 2:11- 1/ “Defendants” refers to both Biogen and Elan when the legal argument is not affected by the role of the individual Defendants. Where the role of the individual Defendants has a bearing on the legal argument, the individual Defendant has been identified. Biogen and Elan collaborated on aspects of the research, development and commercialization of Tysabri. Biogen manufactured the drug, held the FDA license, and had regulatory responsibility for the drug in the United States, and was principally responsible for marketing the drug for MS in the United States. Elan distributed the drug in the United States and also had principal responsibility for the marketing of Tysabri for Crohn’s disease, another approved indication for the drug. Elan was also the license holder for the drug in Europe. (SF ¶5). 2/ This Court granted Defendants’ Motion to Dismiss Plaintiff’s negligent undertaking claim on April 17, 2017. (Dkt. No. 150). 3/ PML refers to Progressive Multifocal Leukoencephalopathy, a viral brain infection caused by the JC virus (“JCV”). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 8 of 49 PageID: 2131 2 cv-01140-DN-DBP, 2016 U.S. Dist. LEXIS 110273 (D. Utah Aug. 5, 2016) (granting summary judgment to Biogen and Elan on a failure to warn claim and all other claims); Amos v. Biogen Idec Inc. & Elan Pharm., LLC, No. 13-cv-6375, (W.D.N.Y. Apr. 10, 2017) (unpublished) (same)4/; Gentile v. Biogen Idec Inc. & Elan Pharm., LLC, No. 1181 CV 03500, 2016 Mass. Super. LEXIS 238 (Mass. Sup. Ct. July 25, 2016) (same). In addition, Plaintiff cannot, on this record, establish the essential element of proximate cause because there is no evidence that any of the alleged inadequacies in the labeling would have changed his neurologists’ prescribing decisions. Finally, federal law preempts Plaintiff’s claim that Defendants should have warned earlier about the significance of the presence of anti-JCV antibodies (i.e., antibodies produced by the immune system to defend against JCV infection). In September 2010, Biogen proposed to FDA’s Center for Drug Evaluation and Research (“CDER”) warning language concerning the significance of anti-JCV antibodies as determined by a related Biogen-developed assay (a blood test). In November 2010, Biogen proposed to FDA’s Center for Devices and Radiological Health (“CDRH”) to make the assay available as a “laboratory developed test” to Tysabri prescribers. both FDA’s CDER and CDRH rejected Biogen’s proposals, both before and after Mr. Nelson’s Tysabri treatment had ended, concluding that the warning and the assay were not sufficiently supported by the then-available scientific evidence. As the Christison, Amos, and Gentile courts held recently, there is “clear evidence” in the undisputed summary judgment record that FDA would not have permitted warnings about the significance of anti-JCV antibodies at any earlier time and indeed at any time before January 2012, when the Agency concluded that the data 4/ Attached as Ex. 100 to Marino Cert. Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 9 of 49 PageID: 2132 3 supported a labeling change. The Plaintiff’s claim under the PLA is thus preempted by federal law. Wyeth v. Levine, 555 U.S. 555, 568 (2009). II. STATEMENT OF UNDISPUTED FACTS A. Andrew Nelson and Multiple Sclerosis. Andrew Nelson suffers from MS, a chronic, progressive, and disabling autoimmune disease of the central nervous system (“CNS”) (the brain, spinal cord, and optic nerves) (Rule 56.1 Statement (“SF”) ¶ 19). In MS, inflammatory white blood cells enter the CNS and attack myelin, a fatty substance that surrounds nerve fibers. (SF ¶ 19). MS causes gradual destruction of the myelin (“demyelination”) throughout the brain and spinal cord, leaving scar tissue called “scleroses,” which can be seen through magnetic resonance imaging. (SF ¶ 20). Depending on where in the CNS the demyelination is located, a broad range of symptoms associated with MS can occur, including loss of muscle control, impaired vision, blindness, incontinence, sensory abnormalities, personality changes, cognitive impairment, and disabling fatigue. (SF ¶ 20). MS is a leading cause of disability, particularly in young people, and most patients require assistance walking if the progression of the disease is not arrested. (SF ¶ 21). In severe cases, MS sufferers can be confined to a wheelchair, bedridden, or die from MS complications. (SF ¶ 21). Mr. Nelson was first diagnosed with MS in 2002. (SF ¶ 6). In 2003, Mr. Nelson’s neurologist, Jana Preiningerova, M.D., prescribed Avonex, a first line MS treatment, to treat Nelson’s multiple sclerosis. (SF ¶ 58). Despite this treatment, Mr. Nelson’s MS was not controlled; between 2003 and 2006, Mr. Nelson experienced a number of MS relapses or “exacerbations” of the disease. (SF ¶ 59). By September 2006, Mr. Nelson was suffering from muscle spasms and dizzy spells, and he began experiencing cognitive difficulties. (SF ¶¶ 62-63). These symptoms continued to worsen over time. (SF ¶ 65). At that point, Dr. Preiningerova recommended more aggressive drug therapy, specifically Tysabri (SF ¶ 66). Dr. Preiningerova Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 10 of 49 PageID: 2133 4 discussed the risk of PML with Mr. Nelson and obtained informed consent to the treatment. (SF¶ 69). She prescribed Tysabri to Mr. Nelson in April 2008, and he began infusions in May 2008. (SF ¶¶ 69-70). After beginning Tysabri treatment under the care of Dr. Preiningerova in New Haven, Connecticut, Mr. Nelson moved to Omaha, Nebraska and continued to receive monthly Tysabri infusions under the care of neurologist Rana Zabad, M.D. (SF ¶ 72). Mr. Nelson did well on Tysabri, with no acute exacerbations of his MS. (SF ¶ 73). Mr. Nelson then moved to New Jersey and in September, 2009, Kenneth Citak, M.D. of Ridgewood, New Jersey became Mr. Nelson’s treating neurologist. (SF ¶ 75). Dr. Citak continued to prescribe Tysabri and Mr. Nelson continued to do well on the drug. (SF ¶ 76). Mr. Nelson remained on Tysabri until his final infusion on September 17, 2010, when Dr. Citak suspended Tysabri treatment in response to symptoms that raised the possibility of PML. (SF ¶¶ 77-79). In December 2010, Mr. Nelson was diagnosed with PML. (SF ¶ 80).5/ B. Tysabri (Natalizumab). Tysabri is a recombinant, humanized, monoclonal antibody that inhibits the trafficking of inflammatory white blood cells into the CNS, and thereby protects myelin from attack and resulting nerve cell damage. (SF ¶ 24). Because of this mechanism of action, Tysabri is highly effective at interrupting the MS disease process, decreasing the number of MS relapses and substantially reducing and delaying nerve damage and resulting disability. (SF ¶¶ 25-26). FDA approved Tysabri in November 2004 for treatment of relapsing forms of MS based on clinical trial data demonstrating Tysabri’s high efficacy in interrupting the MS disease process and reducing disability, combined with a strong safety profile. (SF ¶ 26). 5/ Mr. Nelson was aware of the PML risk. After stopping Tysabri Mr. Nelson stated that Tysabri is “the best of the best drugs, but I would caution anyone to take the risks seriously. I did not because I thought I would never be the one to develop PML. Turns out I was.” (SF ¶ 18). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 11 of 49 PageID: 2134 5 1. PML is a Known Risk of Tysabri. In February 2005, a few months after the drug went on the market, Defendants received reports that two MS patients who were participating in ongoing clinical trials of Tysabri used in combination with Avonex had developed PML. PML had never before been associated with MS, Avonex, or Tysabri. (SF ¶¶ 29). PML is caused by JCV.6/ In response to the reports of the two PML cases in the Tysabri/Avonex-treated MS population, Defendants voluntarily withdrew Tysabri from the market and suspended its use in clinical trials so that the PML risk could be evaluated and quantified. (SF ¶ 34).7/ After months of reviewing the safety data, Biogen sought FDA approval to reintroduce the drug to the market with new labeling concerning the PML risk. (SF ¶ 37). On March 2, 2006, Biogen submitted extensive data to FDA including, among other things, the results of antibody testing of blood serum samples from Tysabri clinical trial patients using an anti-JCV antibody assay developed by the National Institutes of Health (“NIH”). (SF ¶ 38). The report concluded that the data was insufficient and there was no consensus on a clinically relevant cutoff for a “positive” assay result at that time. (SF ¶ 38). FDA convened an Advisory Committee of experts to evaluate the benefit/risk profile of Tysabri in light of the severity of MS and the available treatments and to make a recommendation to FDA as to whether the drug should be available for use in the treatment of MS. After a review of the data and a public hearing at which the experts heard testimony from 6/ JCV is an acronym for “John Cunningham virus.” It is a common and ubiquitous virus that infects the majority of adults. See Christison, 2016 U.S. Dist. LEXIS 110273, *11, ¶ 8. It is generally harmless except in cases of severe immunosuppression resulting from AIDS, immunosuppressive drugs used in treating cancer and in preventing post-transplant tissue rejection, and certain biologic medications that target the immune system. 7/ In the subsequent safety review, a third PML case was identified in a patient in Belgium who was participating in a clinical trial of Tysabri in the treatment of Crohn’s disease. It was determined that the clinical trial investigator had misdiagnosed the patient’s PML as a brain tumor. (SF ¶ 36). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 12 of 49 PageID: 2135 6 MS specialists, patient advocacy groups, and MS patients in support of Tysabri’s return to the market, the Advisory Committee recommended that FDA approve Tysabri’s return to the market with new labeling and certain restrictions on its use. (SF ¶¶ 39-40). On June 5, 2006, FDA accepted the Advisory Committee’s recommendations and approved Tysabri’s return to the market as a monotherapy (i.e., a drug that is taken alone) for relapsing forms of MS, subject to a number of significant new requirements to mitigate the PML risk. (SF ¶ 41).8/ 2. FDA Required a Black Box PML Warning and the TOUCH Prescribing Program. First, FDA mandated that the labeling include a “black box” or “boxed” warning concerning the risk of developing PML. (SF ¶ 43). A “boxed” warning is the strongest warning required or permitted by FDA in prescription drug labeling and highlights particularly important information that physicians must take into account when considering whether to prescribe a drug to a particular patient.9/ (SF ¶ 12). At the time Mr. Nelson was first prescribed Tysabri in May 2008, the black box warning read as follows: WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Although the cases of PML were limited to patients with recent or concomitant exposure to immunomodulators or immunosuppressants, there were too few cases to rule out the possibility that PML may occur with TYSABRI monotherapy [see Warnings and Precautions (5.1)].  Because of the risk of PML, TYSABRI is available only through a special restricted distribution program called the TOUCH™ Prescribing Program. Under the TOUCH™ Prescribing Program, only prescribers, infusion centers, and pharmacies associated with infusion centers registered with the 8/ FDA’s approval letter advised that FDA had reviewed Defendants’ submissions through June 2, 2006, which includes the March 2006 submission discussing NIH’s assay. 9/ See 21 C.F.R. § 201.57(c)(1); 44 Fed. Reg. 37434, 37448 (FDA June 26, 1979) (“[T]o ensure the significance of boxed warnings in drug labeling, they are permitted in labeling only when specifically required by FDA.”); Kaleta v. Abbott Labs., Inc., 87 F. Supp. 3d 916, 924 (S.D. Ill. 2015). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 13 of 49 PageID: 2136 7 program are able to prescribe, distribute, or infuse the product. In addition, TYSABRI must be administered only to patients who are enrolled in and meet all the conditions of the TOUCH™ Prescribing Program [see Warnings and Precautions (5.1, 5.2)].  Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom that may be suggestive of PML. TYSABRI dosing should be withheld immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation that includes a gadolinium-enhanced magnetic resonance imaging (MRI) scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended [see Contraindications (4), Warnings and Precautions (5.1)]. (SF ¶ 14) (emphasis in original). The Tysabri prescribing information also included a “Warnings” section that contained two pages of warnings, in bold print, regarding the PML risk, including the fact that neither the absolute PML risk nor an individual patient’s risk factors can be precisely estimated. The “Warnings” section began: Progressive multifocal leukoencephalopathy, an opportunistic infection caused by the JC virus, and which typically only occurs in patients that are immunocompromised, has occurred in three patients who received TYSABRI in clinical trials [see Boxed Warning]. . . The absolute risk for PML in patients treated with TYSABRI cannot be precisely estimated, and factors that might increase an individual patient’s risk for PML have not been identified. There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs. It is not known whether early detection of PML and discontinuation of TYSABRI will mitigate the disease. There is limited experience beyond two years of treatment. The relationship between the risk of PML and the duration of treatment is unknown.10/ The labeling also contained an “Indications and Usage” section, stating that “TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability . . .” (SF ¶¶ 45-46). Defendants included PML warnings in Tysabri’s Medication Guide, which stated that “PML usually happens in people with weakened immune systems. No one can predict who will 10/ The warning assumes that all patients are or may become infected with the virus. It is not qualified in any way. In fact, suggesting antibody testing at the time would have weakened the black box warning by suggesting, without knowing, that a negative result on the assay meant patients were at lower risk for developing PML. Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 14 of 49 PageID: 2137 8 get PML. There is no known treatment, prevention, or cure for PML.” (SF ¶ 47). A version of the boxed warning, and the numerous other PML warnings, were included in the drug’s labeling throughout the time that Mr. Nelson received 26 monthly Tysabri infusions. (SF ¶ 12, 14). Second, FDA determined that because of the significance of the PML risk, Tysabri would be a “restricted” drug that could only be prescribed, dispensed or used by treating neurologists, specialty pharmacies and patients who are enrolled in a detailed Risk Evaluation and Mitigation Strategy Program (“REMS” program). (SF ¶ 48, 50). The Tysabri REMS program approved by FDA as a condition of the drug’s return to the market is called the “TOUCH” program.11/ In its June 5, 2006 re-approval letter, FDA expressly prohibited Biogen from altering the REMS program’s content without prior FDA approval. (SF ¶ 57). The TOUCH Program was intended to “assess the risk of [PML] associated with [Tysabri], minimize the risk of PML, minimize death and disability due to PML, and promote informed risk-benefit decisions regarding TYSABRI use.” (SF ¶ 52). TOUCH is also designed to ensure that treating neurologists (specialists whose field includes the diagnosis and treatment of both MS and PML) understand the PML risk associated with Tysabri treatment and inform patients of that risk. (SF ¶ 53). Participating neurologists must acknowledge, in writing, that they understand the PML risk. Before prescribing Tysabri and enrolling the patient in the TOUCH program, the physician must also obtain a written acknowledgement from each patient that the patient understands the PML risk.12/ (SF ¶ 53). The TOUCH enrollment form warns about the PML risk, and by signing the patient acknowledges that ‘[m]y chance of getting PML may be higher if I am treated with other medicines that can weaken my immune system, including other 11/ TOUCH is an acronym for Tysabri Outreach: Unified Commitment to Health. 12/ The Tysabri prescribing information in the label included the requirements of the TOUCH program and the prescribing physician’s responsibilities under that program. (SF ¶ 47). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 15 of 49 PageID: 2138 9 MS treatments,” and that “[i]t is also not known if treatment for a long period of time with TYSABRI can increase my chance for PML.” (SF ¶ 15). Mr. Nelson and his physicians enrolled in TOUCH and signed the appropriate forms. (SF ¶ 15, 16). Following enrollment in TOUCH and the initiation of Tysabri treatment, at every monthly Tysabri infusion thereafter specially trained infusion nurses enrolled in the TOUCH program must obtain the patient’s acknowledgement and confirmation that the patient has read the Medication Guide, which includes the warnings concerning the PML risk associated with Tysabri that are set forth in the drug’s labeling. (SF ¶ 54, 55). The infusion nurse must ask the patient a series of questions about the patient’s knowledge of the PML risk and inquire about the emergence of any new symptoms that suggest a change in neurologic condition that could possibly be an early sign of PML. If any such changes are reported, the Tysabri infusion cannot be given without further evaluation and approval by the prescribing neurologist. (SF ¶¶ 54-56). C. Defendants’ Pharmacovigilance Efforts Led to the Discovery of Three PML Risk Factors that Resulted in Amendments to Tysabri’s PML Warnings. After the initial PML cases were reported in February 2005, Defendants embarked on a broad-based research program and, in regular communication with FDA, maintained an intensive pharmacovigilance protocol to study and better understand PML. The focus of these efforts was to determine whether there was any way to “stratify” the PML risk (i.e., to identify individual risk factors for PML that a physician could use in making prescribing decisions and in counseling patients). (SF ¶ 34-35). Specifically, Defendants sought to determine why a small number of Tysabri patients get PML when the majority of Tysabri patients are infected with JCV, but do not get PML. Between 2008 and 2012, as a result of growing use and experience with Tysabri and Tysabri-associated PML, three individual risk factors were identified and quantified: (1) duration Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 16 of 49 PageID: 2139 10 of Tysabri treatment; (2) prior treatment with immunosuppressant drugs; and (3) the detection of anti-JCV antibodies in blood, using an FDA-cleared assay that Biogen scientists developed and analytically and clinically validated for use with Tysabri. 13/ (SF ¶¶ 103, 107-108, 141). 1. In November 2009, While Mr. Nelson was Prescribed Tysabri, FDA Approved a Label Update to Include the Duration of Treatment as a PML Risk Factor. At the time Tysabri returned to the market in June 2006, Defendants and FDA considered whether the PML risk might be associated with duration of Tysabri treatment—with the risk increasing with longer treatment duration—but there were insufficient data to support any conclusion.14/ (SF ¶ 101). This uncertainty was stated expressly in the Tysabri label. (SF ¶ 101). After the two cases of PML in MS patients reported in the clinical trials before Tysabri’s return to the market (and a third case in a Crohn’s disease patient (SF ¶ 45, 101)), there were no additional confirmed cases of Tysabri-associated PML for Defendants to analyze until July 2008. At that time, the first two Tysabri-associated cases occurring after Tysabri’s re- introduction to the market were confirmed.15/ (SF ¶ 99, 101). In August 2008, at Biogen’s request, FDA approved an update to the Tysabri labeling to explain that: “There is limited experience beyond two years of treatment. The relationship between the risk of PML and the 13/ “Analytically validated” in this case means a JCV antibody assay that has been shown to accurately detect JCV antibodies to prove prior exposure to the JC virus. (SF ¶ 124). “Clinically validated” in this case means a JCV antibody assay that has been shown through clinical trial data to be useful to physicians in the clinical setting by providing information regarding the association of JCV antibodies to an individual’s PML risk. Clinical validation is an FDA requirement for any labeling claim or the marketing of any drug or device for use in the diagnosis or treatment of a disease. (SF ¶ 125). 14/ Two of the three PML cases occurred after a median of 120 weeks of treatment, while the third occurred after 32 weeks of treatment. (SF ¶ 29). 15/ At the time Dr. Preiningerova first prescribed Tysabri to treat Mr. Nelson’s MS, and throughout the time that she treated Mr. Nelson, the label stated that individual risk factors that predispose a person to the development of PML are unknown and that the absolute risk of developing PML cannot be precisely estimated. (SF ¶ 45). While Dr. Preiningerova treated Mr. Nelson in Connecticut before he moved to Nebraska in July 2008, there were no additional PML cases and no changes in the information available concerning Tysabri and PML (SF ¶ 68). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 17 of 49 PageID: 2140 11 duration of treatment is unknown, but most cases of PML were in patients who received more than one year of treatment.” (SF ¶ 103). Over time, confirmed PML cases reported to Biogen increased in number and in frequency. In September 2009, Biogen and FDA both independently concluded, based on analyses of the post-marketing PML cases, that longer duration of Tysabri treatment increases the PML risk. Based on that data, and at Biogen’s request, FDA approved an update to the Tysabri label in November 2009 to read: “In patients treated with TYSABRI, the risk of developing PML increases with longer treatment duration, and for patients treated for 24 to 36 months is generally similar to the rates seen in clinical trials. There is limited experience beyond 3 years of treatment.” (SF ¶ 103). This updated language was in the Tysabri label from that point on and throughout the time that Dr. Citak prescribed the drug to Mr. Nelson. 2. In July 2010, While Mr. Nelson was Prescribed Tysabri, FDA Approved a Label Update to Include Prior Treatment with an Immunosuppressant Drug as a PML Risk Factor. Defendants continued to analyze all PML cases for additional possible individual risk factors and, in July 2010, FDA approved Biogen’s proposed update to the Tysabri label to reflect Biogen’s conclusion that prior treatments with immunosuppressant drugs is an independent PML risk factor. (SF ¶ 108). The amended labeling stated: “The risk of PML is also increased in patients who have been treated with an immunosuppressant prior to receiving Tysabri. This increased risk appears to be independent of Tysabri treatment duration.” (SF ¶ 108). This language was in the label from that point on and throughout Dr. Citak’s treatment of Mr. Nelson’s MS with monthly Tysabri infusions. Mr. Nelson was never treated with immunosuppressant drugs prior to his Tysabri treatment (SF ¶ 85). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 18 of 49 PageID: 2141 12 3. Biogen Researched and Developed an Assay to Test for the Presence of Anti-JCV Antibodies and Concluded that a Positive Assay Result is a Marker of Increased PML Risk. It is basic medical knowledge that PML is caused by the JC virus and this fact was stated in the Tysabri label when FDA approved its return to the market in 2006. (SF ¶¶ 31-32, 45). It is also common scientific knowledge that the presence of anti-JCV antibodies is biologic evidence that a person has been exposed to JCV. (SF ¶ 115). FDA was aware of this information when it evaluated Tysabri before its return to the market in 2006. In fact, FDA requested that Biogen conduct an assessment for the presence of JCV antibody at baseline for patients entering clinical trials. (SF ¶ 37). On March 2, 2006, Biogen submitted to FDA a report on the results of antibody testing of serum samples conducted at the NIH, which was inconclusive. (SF ¶ 38). When Tysabri was approved to return to the market in 2006, there were no statistically significant data from which to determine whether the presence of anti-JCV antibodies indicated whether someone is at a higher or lower risk of getting PML. (SF ¶ 118). Although a positive finding on a JCV antibody assay would indicate a necessary prerequisite to JCV infection, without data, a positive finding could not be used as evidence of a relatively higher PML risk and a negative finding could not be used as evidence of relatively lower PML risk. (SF ¶ 119).16/ By late 2009, Biogen scientists had developed an analytically validated antibody assay that could reliably detect circulating anti-JCV antibodies in the blood with acceptably low false- positive and false negative rates. (SF ¶ 123). Using this assay, Biogen scientists developed data 16/ From the time Tysabri was removed from the market in 2005 through 2010, Defendants’ scientists and others in the field also pursued what they thought to be the most likely risk stratification tool by devoting research efforts to finding JC virus DNA in the blood through Polymerase Chain Reaction (PCR) assay testing. (SF ¶ 112). PCR testing was thought to be the most likely risk stratification tool because, to develop PML, a person must be infected with the JC virus and the virus must move through the body to the CNS and must mutate into a form that can replicate in CNS tissue. (SF ¶ 112). By 2010, PCR testing was found “unlikely to be useful” as a PML risk stratification tool in data published in the Annals of Neurology. (SF ¶ 112). Christison, 2016 U.S. Dist. LEXIS 110273, at *46. Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 19 of 49 PageID: 2142 13 from a small number of PML cases for which pre-PML blood serum samples were available for testing that suggested the presence of circulating antibodies might be a predictive indicator or “marker” of higher relative PML risk. (SF ¶ 129). Specifically, Biogen discovered that 100% (11 of 11) patients for whom pre-PML blood samples were available for testing had detectable anti- JCV antibodies using an assay that would predict (based on population studies of the prevalence of JCV antibodies using the assay) a rate of exposure to JCV among the MS population of 54%. (SF ¶ 129). Biogen therefore convened Advisory Boards of MS experts and regulatory experts to evaluate these findings. (SF ¶ 127). At an Advisory Board meeting on December 9, 2009, the experts opined that the “data on the assay was too preliminary to be of predictive value” regarding PML. (SF ¶ 127). In an Advisory Board meeting on December 12, 2009, most (but not all) of the medical experts agreed that, based on the limited data available, the idea of using anti- JCV antibody testing in risk stratification had potential, and that Biogen should pursue further research in this area. (SF ¶ 128). Defendants’ scientists continued to search for pre-PML serum samples (blood samples drawn and stored before the patient was diagnosed with PML and that remained available for testing) from physicians around the world to collect more data regarding anti-JCV antibodies in PML patients and the prevalence of antibodies in the MS patient population (“seroprevalence”) generally. They also continued to work on improving the sensitivity and specificity of the anti-JCV antibody assay, i.e., minimizing false negatives and false positives. Ultimately Biogen had data from testing 17 pre-PML blood samples that supported the hypothesis that circulating anti-JCV antibodies could be a predictive biomarker of increased PML risk in Tysabri-treated MS patients. (SF ¶ 133). Biogen published these results in September 2010. (SF ¶ 133). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 20 of 49 PageID: 2143 14 4. In September 2010, FDA Rejected Biogen’s Proposal to Change Tysabri’s Label to Reference Anti-JCV Antibody Testing. Based on this data, on September 8, 2010, representatives of Biogen and Elan met with regulators at FDA’s CDER to discuss a potential labeling change based on Defendants’ ongoing research regarding the significance of anti-JCV antibodies. (SF ¶ 131). Specifically, Biogen proposed to amend the label to recommend that patients be screened for the antibodies using the Biogen-developed assay and that the results of that screening be used as one factor in the neurologists’ benefit/risk evaluation of Tysabri treatment in individual patients. (SF ¶ 131). FDA rejected the proposal. As detailed in FDA’s official meeting minutes, FDA concluded that the then-available scientific data were insufficient to support inclusion of a warning about the significance of anti-JCV antibody status in Tysabri’s labeling: Sponsor Question 5: Does the Agency agree that the proposed labeling concepts reflect the information that should be provided in the prescribing information for TYSABRI? The proposed labeling concepts are as follows:  Individual anti-JCV antibody status is one consideration in determining the benefit/risk of TYSABRI  Screening for serum anti-JCV antibody should be performed prior to initiating therapy and annually thereafter  Patients who are anti-JCV negative have a lower risk of developing PML than those who are anti-JCV antibody positive  There is an increased risk for PML in anti-JCV antibody positive patients FDA Pre-Meeting Comments: As discussed in the answers above, the Division does not believe that there is currently sufficient information to support the clinical utility of the anti-JCV antibody assay in determining the risk for PML and the benefit/risk of TYSABRI. The Division does, however, agree that the test may be promising and that it should [be] studied carefully to address the concerns identified in our responses. (SF ¶ 132) (emphasis added). FDA concluded that the data did not support a labeling change concerning anti-JCV antibody testing because there was not a sufficient number of PML cases for which Biogen had Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 21 of 49 PageID: 2144 15 pre-PML blood samples available for testing. (SF ¶ 132). FDA stated that it was “too early” in the analysis of this methodology “to determine the value of this marker as a PML risk stratification tool.” (SF ¶ 132). FDA was also concerned that the samples Biogen used in its testing were selected retrospectively, rather than being drawn prospectively. (SF ¶ 132). FDA’s official meeting minutes reflect this and numerous other concerns regarding the data available as of September 2010 and Biogen’s proposed labeling change:  “The results are based on only a small population (only 17 patients had pre-PML antibody status tested)”;  “It appears that the results you describe are based on testing that was done after patients had already been exposed to Tysabri. It would be more useful, in determining the value of the test, if there were results of serial anti-JCV antibody tests for patients beginning before exposure to Tysabri and then at fixed times following administration of Tysabri (e.g. to identify whether rising antibody titers are predictive of PML)”;  “It is not clear how these results would guide therapy in antibody positive patients”;  “Based on this we are concerned about the stability of the determination, and the utility in using it to predict development of PML”;  “We do not agree that the proposed data package is sufficient to demonstrate the clinical utility of the anti-JCV antibody assay.  “Based on the information you have presented, antibody-negative patients would have a lower risk of developing PML. It is not clear how this information would help guide therapy, particularly given the uncertainty related to the stability of the result in a given individual over time.”17/ (SF ¶ 132). 17/ A patient may test “negative” for the presence of antibodies to the JC virus and then test positive on a subsequent test, and vice versa. This could be the result of subsequent first exposure to the common and ubiquitous virus, or the result of a false negative or false positive test. This phenomenon is referred to as “seroconversion.” The current label states that the rate of seroconversion is between 3% and 8%, and therefore recommends periodic retesting. Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 22 of 49 PageID: 2145 16 5. In November 2010, FDA Also Rejected Biogen’s Proposal to Make the Anti-JCV Antibody Assay Available to Tysabri Prescribers. On November 18, 2010, Defendants again met with FDA regulators, this time at FDA’s CDRH, the FDA division responsible for diagnostic tests and medical devices. They discussed Biogen’s proposal to make Biogen’s anti-JCV antibody assay available to Tysabri prescribers as a “laboratory developed test” (“LDT”) kit before FDA clearance of the Biogen assay and related Tysabri labeling changes. (SF ¶ 134). FDA again rejected Biogen’s proposal and reiterated in the official meeting minutes FDA’s conclusion that “[t]he usefulness of this test in treatment with Tysabri has not been established.” (SF ¶ 135). FDA further stated that the assay could not be made available for use with Tysabri until both (1) the antibody assay was cleared by FDA for use in the clinical setting as a medical device, and (2) a labeling change for Tysabri was approved after the submission of clinical data demonstrating the “clinical utility” of an assay finding (positive or negative) to the physician’s evaluation of an individual patient’s PML risk. (SF ¶ 135). FDA’s official meeting minutes document FDA’s multiple concerns regarding the sufficiency and significance of the assay data and its usefulness to physicians in prescribing Tysabri, stating among other comments:  “This specific assay does not have any intended use other than to be used with the drug. Therefore, an LDT could not be cleared/approved before the assay is mentioned in the drug label”;  “The Agency confirmed that an LDT clearance for the proposed indications could only take place after the clinical division had approved the label change that described the clinical utility of the assay”;  “If the drug labeling specifies this device as critical in order to determine therapy, the sponsor/test must comply with FDA regulations for in vitro diagnostic devices”;  “The information provided does not allow us to determine the clinical utility for the intended use claims”; Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 23 of 49 PageID: 2146 17  “[t]he anti-JCV antibody assay has limited positive predictive value . . .”; and  “Your proposal to assess the agreement between your commercial kit and your LDT test (which is essentially the same device) is not acceptable as a means to evaluate your device performance. As stated above, we recommend that you assess the clinical performance of your device in the context of the drug trial.” (SF ¶ 136). In light of FDA’s rejection of Biogen’s proposals to change the label and to make the assay available to neurologists as an LDT, Biogen continued its search for pre-PML samples in patients diagnosed with Tysabri-associated PML. Beginning in March 2010, Biogen sponsored two prospective clinical trials of the anti-JCV antibody assay, STRATIFY I and STRATIFY II. (SF ¶ 137-138). 6. After the Two Clinical Trials and the Submission of Additional Data, FDA Approved an Amendment to Tysabri’s Label Concerning the Significance of Anti-JCV Antibodies in January 2012. In October 2011, Biogen presented to FDA additional data that it had developed in connection with its ongoing research and evaluation of PML cases for which pre-PML serum samples were available for testing, and data developed in the two clinical trials. (SF ¶ 139). Biogen again requested that the Tysabri label be amended to include information concerning the significance of detectable anti-JCV antibodies using the Biogen-developed assay. (SF ¶ 139). On January 20, 2012, FDA publicly announced that it had cleared Biogen’s STRATIFY JCV Antibody Assay for use with Tysabri treatment and approved an associated Tysabri labeling change to reflect this information. (SF ¶ 141). D. Plaintiff’s Complaint. On November 28, 2012, Plaintiff commenced this action against Biogen and Elan. In the sole remaining claim in this case, Plaintiff has asserted three alleged deficiencies in the FDA- approved black box warning and related labeling concerning the PML risk during the period Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 24 of 49 PageID: 2147 18 when he received Tysabri infusions, between 2008 and 2010. These alleged deficiencies mirror the changes that have been made to the Tysabri label since the drug was re-launched in 2006. Specifically, Plaintiff alleges a failure to adequately warn about the risk of PML associated with (1) duration of treatment, (2) prior immunosuppressant treatment, and (3) the significance of anti-JCV antibody assay results. Fourth Amend. Compl. ¶ 87. Plaintiff cannot prevail on any of these warnings claims and summary judgment must enter in Defendants’ favor under Rule 56 as a matter of law. III. ARGUMENT A. Choice of Law. Plaintiff brought his failure to warn claim under the PLA, and the Parties do not dispute that New Jersey law applies to Mr. Nelson’s claim. See ECF No. 50, “Plaintiff’s Opposition to Motion To Dismiss Second Amended Complaint,” at 3 (“Consequently, Plaintiff maintains that Count II, the failure to warn claim under the New Jersey Products Liability Act is properly pled and meets Federal Court pleading standards.”). B. Summary Judgment Standard. Federal courts must grant summary judgment when “there is no genuine dispute as to any material fact” (Fed. R. Civ. P. 56(a)) or when a plaintiff “fails to make a showing sufficient to establish the existence of an element essential to that party’s case, and on which that party will bear the burden of proof at trial.” Celotex Corp. v. Catrett, 477 U.S. 317, 322 (1986). Summary judgment is appropriate where, drawing all reasonable inferences in favor of the non-moving party, “there is no genuine dispute as to any material fact and the movant is entitled to judgment as a matter of law.” Fed. R. Civ. P. 56(a); see also Celotex Corp., 477 U.S. at 322-23. “An issue is genuine only if there is a sufficient evidentiary basis on which a reasonable jury could find for the non-mov[ant.]” Kaucher v. Cnty. of Bucks, 455 F.3d 418, 423 (3d Cir. 2006) (citing Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 25 of 49 PageID: 2148 19 Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 248 (1986)). “In response to a properly-supported motion for summary judgment, the non-moving party must point to some evidence in the record that creates a genuine issue of material fact and must rebut the motion with facts in the record and cannot rest solely on assertions made in the pleadings, legal memoranda, or oral argument.” Grobelny v. Baxter Healthcare Corp., 341 F. App’x 803, 806 (3d Cir. 2009) (internal quotations omitted). Summary judgment is available if the party with the burden of proof at trial fails to present in the summary judgment record, taking everything it says as true and drawing all reasonable inferences in its favor, sufficient facts to warrant a finding in its favor. Anderson, 477 U.S. at 248. C. Defendants are Entitled to Summary Judgment Because—as Three Courts Have Decided—Tysabri’s Warnings Concerning the PML Risk with Tysabri Treatment are Adequate as a Matter of Law. 1. Tysabri’s FDA-Approved PML Warnings are Presumed Adequate. To succeed on his single failure to warn claim under New Jersey’s PLA, Plaintiff must prove that Tysabri “failed to contain adequate warnings.” N.J.S.A. § 2A:58C-2. A manufacturer is not liable if the “product contains an adequate warning or instruction.” N.J.S.A. § 2A:58C-4.18/ The PLA imposes a presumption that an FDA-approved label is adequate as a matter of law. N.J.S.A. § 2A:58C-4. The PLA defines the presumption of adequacy: In any product liability action the manufacturer or seller shall not be liable for harm caused by a failure to warn if the product contains an adequate warning or instruction or, in the case of dangers a manufacturer or seller discovers or reasonably should discover after the product leaves its control, if the manufacturer or seller provides an adequate warning or instruction. . . . If the warning or instruction given in connection with a drug or device or food or food additive has been approved or prescribed by the federal Food and Drug Administration under the “Federal Food, Drug, and Cosmetic Act,” 52 Stat. 1040, 21 U.S.C. 301 et seq. or the “Public Health Service Act,” 58 Stat. 682, 42 18/ An adequate warning is one that a reasonably prudent person in the same or similar circumstances would have provided. Zaza v. Marquess and Nell, Inc., 675 A.2d 620, 632 (N.J. 1996). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 26 of 49 PageID: 2149 20 U.S.C. § 201 et seq., a rebuttable presumption shall arise that the warning or instruction is adequate. N.J.S.A.§ 2A:58C-4 (emphasis added). New Jersey courts have held that the “presumption is a ‘super presumption’ and ‘only in the ‘rare case’ will damages be assessed against a manufacturer issuing FDA-approved warnings.’” In re: Accutane Litig., No. 271 (MCL), 2015 N.J. Super. Unpub. LEXIS 1216, at *32 (N.J. Super. Ct. April 2, 2015) (quoting Kendall v. Hoffman-La Roche, Inc., 36 A.3d 541, 554-555 (N.J. 2012)) (additional citation omitted). In fact, courts have held that FDA-approved labeling should be virtually dispositive of failure to warn claims under New Jersey law. Perez v. Wyeth Labs., Inc., 734 A.2d 1245, 1259 (N.J. 1999). The purpose of the PLA is to limit the liability of manufacturers, and the super presumption guards against lay juries second-guessing FDA’s medical judgments about warning adequacy and safety in FDA-approved drugs. See Rowe v. Hoffman-La Roche, Inc., 917 A.2d 767, 772, 774 (N.J. 2007); see also Seavey v. Globus Med. Inc., No. 11-cv-2240, 2014 U.S. Dist. LEXIS 65985, at *20 (D.N.J. Mar. 11, 2014) (“The New Jersey legislature recognized the role of federal regulation of drugs and medical devices by including in the PLA a rebuttable presumption that labelling is adequate when a manufacturer includes a warning that complies with FDA requirements.”); In re: Accutane Litig., 2015 N.J. Super. Unpub. LEXIS 1216, at *33. Here, Tysabri’s FDA-approved “black box” and other PML warnings are presumptively adequate under New Jersey law. PML is a known risk of Tysabri. Before Tysabri’s 2006 reentry to the market, FDA carefully considered the PML risk and mandated that Tysabri’s labeling include a specific black box warning informing prescribers about Tysabri’s PML risk. FDA also mandated the TOUCH prescribing program to reinforce this warning. (SF ¶ 48). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 27 of 49 PageID: 2150 21 There is no record evidence that Biogen or Elan had knowledge of the later-added risk factors of duration of treatment, prior immunosuppression and the significance of anti-JCV antibodies before FDA approved Biogen’s requests that the labeling be updated to add these PML risk factors. On the same undisputed record, the Christison court held that Tysabri’s “unmistakable” PML warnings reflected the scientific knowledge available at the time: [A] warning on a prescription drug should be evaluated as a whole and not through the nitpicking prism of an interested legal advocate after the fact . . . when read as a whole, the warning conveys a meaning as to the consequences that is unmistakable. Here, the Tysabri label clearly conveys a warning that taking Tysabri would increase the risk of PML, and that due to the preliminary nature of the research in 2006, there was no reliable correlation between length of treatment, use with other immunosuppressant drugs, or a positive indication of JC Virus antibodies. [Plaintiff’s] request that that information be placed on the label is aided by hindsight rather than the scientific information available at the time. 2016 U.S. Dist. LEXIS 110273, at *75 (italics in original) (internal quotations omitted); see also Amos, No. 13-cv-6375, (W.D.N.Y. Apr. 10, 2017) (unpublished). Moreover, once Defendants established sufficient data showing the duration and then the prior immunosuppressant use risk factors, they went to FDA and FDA approved the addition of these risk factors to the Tysabri label. (SF ¶107, 108).19/ Plaintiff cannot point to any evidence in the summary judgment record that could demonstrate that Defendants had earlier knowledge of statistically significant data before the PML risk factors were added to Tysabri’s label. 19/ Plaintiff cannot rely on evidence of the Tysabri labeling changes to prove an alleged failure to warn. Fed. R. Evid. 407. Rule 407 precludes the use of “subsequent remedial measures” to impose liability. The Superior Court of New Jersey, Appellate Division, vacated a final judgment and remanded a case for a new trial where the trial court permitted evidence that the Accutane label was changed after plaintiff stopped taking the drug. Rossitto, 2016 N.J. Super. Unpub. LEXIS 1714, at *46-47. Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 28 of 49 PageID: 2151 22 2. Tysabri’s PML Warnings Informed Plaintiff’s Treating Neurologists of the Precise Risk That is the Basis of Plaintiff’s Failure to Warn Claim. The undisputed summary judgment record also establishes that Plaintiff cannot prevail on a failure to warn claim because, even without the benefit of a statutory presumption, Tysabri’s PML warnings were adequate as a matter of law. Throughout Mr. Nelson’s Tysabri treatment, the Tysabri warnings fully disclosed the risk of the precise harm suffered by Mr. Nelson (PML), the cause of the harm (JCV), the treatment options should the risk eventuate (none), and the likely potential outcome or consequences of the risk eventuating (death or severe disability). Moreover, in addition to the boxed warning, Plaintiff’s neurologists were informed extensively about the PML risk through the TOUCH program. They could only prescribe the drug after enrolling in the TOUCH program, acknowledging in writing that they understood the PML risks, enrolling their patients in the TOUCH program, and completing the TOUCH program forms and requirements. These unusual and robust prescribing requirements strongly reinforce the severity of the PML risk described in detail in the label. The warnings could not have been more clear, consistent, or forceful to warn physicians prescribing Tysabri of the PML risk and the severity of that risk. On the identical FDA regulatory record, the Christison, Amos, and Gentile courts all held that Tysabri’s PML warnings in effect during the relevant time period were adequate as a matter of law. As the Christison court reasoned: “[t]hroughout the label, the risk of PML is highlighted . . . [T]he black box warning explains that Tysabri increases the risk of PML, which ‘usually leads to death or severe disability.’ The label does not qualify or minimize the risk of PML and explains the limitations under which Tysabri may be taken.” 2016 U.S. Dist. LEXIS 110273, at *72. Similarly the Amos court held that “[e]ven without the additional information regarding specific risk factors, the warnings for Tysabri clearly, directly, and unequivocally informed Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 29 of 49 PageID: 2152 23 treating physicians of the increased risk for PML and the seriousness of that condition.” Amos, No. 6:13-cv-06375 at *13. And finally, the Gentile court held that the black box warning “explicitly warned against the precise risk (developing PML) that [plaintiff] ultimately suffered, and fully disclosed the serious consequences of that disease.” 2016 Mass. Super. LEXIS 238, at *16. “[W]hen a plaintiff claims to be injured in a manner that is addressed by warnings provided to his physician, summary judgment is granted on failure to warn claims.” Id. at *15 (citing Alston v. Caraco Pharm. Inc., 670 F. Supp. 2d 279, 284 (S.D.N.Y. 2009)). New Jersey courts have also held that FDA-approved warnings that expressly warn of the precise injury suffered by a plaintiff are adequate as a matter of law. In re: Accutane Litigation, 2015 N.J. Super. Unpub. LEXIS 1216, at *20 (granting defendant summary judgment under New Jersey law). The Accutane court reasoned, in language that applies equally here, that: Taken as a whole, the warning system crafted by Defendants conveys a meaning as to potential risks and consequences that is unmistakable. It is inconceivable to this court that the reasonable dermatologist (or any physician, generally) of ordinary education, training and experience could examine the materials comprising the warning literature and not immediately conclude that Accutane has been associated with life-altering side effects, including IBD. Id. at *36-37; see also, Gaynor v. Merck Sharp & Dohme Corp., No. 12-1492, 2014 U.S. Dist. LEXIS 82003, at *33-34 (D.N.J. June 17, 2014) (applying New York law, the court held that “when a plaintiff claims to be injured in a manner that is addressed by warnings to his physician, summary judgment is granted on failure to warn claims.”). D. Defendants Are Entitled to Summary Judgment Because Without Competent Expert Testimony From a Neurologist on the Alleged Inadequacy of the FDA- Approved Label, Plaintiff Cannot Prove the Label was Inadequate. 1. Plaintiff’s Expert Does Not Opine About the Adequacy of Tysabri’s Label. Plaintiff’s Complaint contains numerous allegations, but the crux of Plaintiff’s claim is that Tysabri’s labeling failed to adequately warn of the three risk factors that Defendants Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 30 of 49 PageID: 2153 24 determined over time increased the risk of PML. Plaintiff cannot prove that Tysabri’s PML warnings were inadequate because he offers no expert opinion testimony on the adequacy of the label. Plaintiff must prove that Tysabri’s boxed warning and related PML warnings were insufficient to inform his neurologist of the PML risk so that he/she could safely prescribe the drug, thus rendering the drug defective. N.J.S.A. § 2A:58C-2. Under New Jersey’s formulation of the generally recognized “learned intermediary rule,” a drug manufacturer’s duty is to adequately warn the prescribing physician of the risks associated with the drug, not the patient. Seavey, 2014 U.S. Dist. LEXIS 65985, at *32 (emphasis added); Banner v. Hoffman-La Roche Inc., 891 A.2d 1229, 1236 (N.J. App. Div. 2006); Niemiera v. Schneider, 555 A.2d 1112, 1117 (N.J. 1989). Plaintiff cannot prove a failure to warn claim without competent and relevant expert testimony from a physician, in this case a neurologist who treats MS. Expert opinion testimony from a neurologist is necessary because a lay jury could not possibly determine the adequacy of the extensive PML warnings based on the jurors’ common experience. Christison, 2016 U.S. Dist. LEXIS 110273, at *62-63 (“A lay jury would not be able to determine by calling upon their own life experiences and would be speculating in making findings about the adequacy of the Tysabri warning label, which warned extensively about PML. Therefore, there must be expert testimony that the [defendant’s conduct] probably caused the injury.”) (internal citations and quotations omitted); see also Jones v. Synthes USA Sales, LLC, No. 08-cv-2060, 2010 U.S. Dist. LEXIS 85744, at *11, *32-33 (D.N.J. Aug. 19, 2010) (granting summary judgment to defendants on a failure to warn claim because no expert testimony supported plaintiffs’ criticisms of the warnings and plaintiffs must rely “upon expert testimony to establish liability under either an Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 31 of 49 PageID: 2154 25 alternative design or inadequate warning theory.”); Grobelny v. Baxter Healthcare Corp., No. 05-cv-4645, 2008 U.S. Dist. LEXIS 41115, at *4-5 (D.N.J. May 23, 2008) (expert testimony is “required to support a claim when the subject matter is so esoteric that jurors of common judgment and experience are unable to make a determination without the benefit of the information and opinions possessed by a person with specialized knowledge.”); Appleby v. Glaxo Wellcome, Inc., No. 04-cv-0062, 2005 U.S. Dist. LEXIS 32875 (D.N.J. Dec. 13, 2005) (granting summary judgment where plaintiff’s experts failed to show that the defendant’s warning was inadequate); see also Rowland v. Novartis Pharms. Corp., 34 F. Supp. 3d 556, 572 (W.D. Pa. 2014) (“In the prescription drug arena, expert medical testimony is generally required ‘to determine whether the drug manufacturer’s warning to the medical community is adequate because prescription drugs are likely to be complex medicines, esoteric in formula and varied in effect.’”) (citation omitted); Gentile, 2016 Mass. Super. LEXIS 238, at *18 (“When evaluating failure to warn claims, the court must [a]lways bear [ ] in mind that the warning is to be read and understood by physicians, not laypersons. Because the adequacy of the warnings cannot be evaluated by a layperson, expert testimony is necessary to resolve the issue.” (internal citations and quotations omitted)). As the Christison and Gentile courts held after reviewing the same expert report and expert testimony, Plaintiff’s sole liability expert, Eugene Major, Ph.D. (“Major”), does not opine anywhere in his report or in his deposition testimony on the adequacy of the extensive PML warnings in the Tysabri labeling and is, in any event, not qualified to do so.20/ Major does not use the words “warning” or “label” anywhere in his report, and he never describes the language that 20/ Major’s deposition testimony is the same in this case as in Christison and Gentile. Defendants deposed Major once, and the parties agreed that the testimony applies in this case. Major’s report includes a few irrelevant paragraphs discussing a JCV PCR test of Mr. Nelson. Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 32 of 49 PageID: 2155 26 he contends should have been in the label to make it adequate. (SF¶¶ 148, 153).21/ Major also offers no testimony concerning duration of treatment or prior immunosuppressive treatment that would support a failure to warn claim. Although Major asserts that Biogen could have developed an anti-JCV antibody assay earlier, he offers no testimony that Defendants had knowledge that circulating anti-JCV antibodies could be a biomarker to predict increased PML risk.22/ In Christison, the court granted summary judgment to Biogen and Elan on each cause of action “due to [plaintiff’s] failure to provide expert testimony regarding causation and the adequacy of the Tysabri label.” 2016 U.S. Dist. LEXIS 110273, at *66. Similarly, in Gentile, the court found that “plaintiff has failed to provide evidence establishing that a genuine issue of material fact exists regarding the adequacy of the warnings.” 2016 Mass. Super. LEXIS 238, at *18. The court decided that “[b]ecause Dr. Major’s testimony does not create a dispute of material fact regarding whether Tysabri’s warnings were adequate to convey to a prescribing 21/ All that Major says in his report and deposition testimony is that Defendants should have informed doctors and their patients (through the TOUCH Program), that JCV causes PML, and only patients who have been exposed to JCV can get PML. Major asserts that this information “might” have been useful. Defendants’ duty, however, is to warn the physician, so Major’s opinion as to what Defendants should have told patients directly is irrelevant. Moreover, as Major admitted, a neurologist treating MS with Tysabri would be expected to know the basic biologic fact that PML is caused by JCV. Defendants have no duty to instruct physicians on basic medical knowledge or how to practice medicine. Spychala v. GD Searle & Co., 705 F. Supp. 1024 (D.N.J. 1988). 22/ Major admitted that it was not known at the time whether antibodies would be protective, and thus an indicator of lower risk, or whether PML was caused by first-time or “primary” exposure to the ubiquitous virus while a patient was being treated with Tysabri. (SF ¶ 117). He also conceded that (and the Christison court found) in the time before Mr. Nelson’s discontinuation of Tysabri in September 2010, there were no published statistically significant data correlating the presence of anti-JCV antibodies with individual PML risk until Biogen’s September 2010 publication. (SF ¶ 118, Major depo., at 411:16-415:18, 418:20-420:8; Christison, 2016 U.S. Dist. LEXIS 110273, at * 44, ¶ 81). FDA determined that the data were not sufficient to support a labeling change concerning the significance of anti-JCV antibodies until January 2012. Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 33 of 49 PageID: 2156 27 physician the risk of developing PML, plaintiff has failed to establish an entitlement to relief on his failure to warn claim.” Gentile, 2016 Mass. Super. LEXIS 238, at *20. 2. Plaintiff’s Expert is Not Qualified to Opine About the Adequacy of the Tysabri Label. Major is also not qualified to opine about the adequacy of Tysabri’s label.23/ Major specifically testified that he is not a medical doctor, that he does not know the requirements of drug labeling, and that he is not qualified to and will not offer any opinions concerning the adequacy of Tysabri’s label: Q. And could the drug company say anything in its labeling about the use of such assays in connection with prescribing a drug? A. You know, I – I’m not qualified to answer what goes on labeling of a prescription drug. *** Q. Is it your belief that Biogen Idec and Elan should have recommended to physicians in the labeling that they do antibody testing? A. It was certainly my recommendation that many steps be taken to understand what’s going on in these patients. I’m not going to comment on the labeling. (SF ¶¶147-149). Based on this testimony, the Christison court held: “It could not be clearer. Dr. Major himself stated that he is not qualified to answer what goes on labeling of a prescription drug.” Christison, Dkt. 195, at 524/ (internal quotations omitted); see also Christison, 2016 U.S. Dist. LEXIS 110273, at *64 (plaintiff “does not have a qualified expert to testify on what ‘a more adequate label’ would contain”). In Gentile, the court also found on this record that Major (1) is not familiar with the requirements for labeling for prescription drug; (2) is not a medical doctor; 23/ Defendants address Major’s lack of qualifications more fully in their Joint Motion in Limine to Exclude Major, filed contemporaneously with this Memorandum. 24/ Attached as Ex. 101 to Marino Cert. Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 34 of 49 PageID: 2157 28 (3) does not have the qualifications necessary to opine on matters of treating patients; and (4) does not assert that he has the experience necessary to interpret warnings from the perspective of a prescribing physician. 2016 Mass. Super. LEXIS 238, at *20. Thus, “even if Dr. Major were prepared to testify about the adequacy of the warnings, his opinion would be inadmissible.” Id. E. Plaintiff Cannot Prove Proximate Cause Because Plaintiff Cannot Meet His Burden of Proving that His Neurologists Would Not Have Prescribed the Drug Had the PML Warnings Been Different. Mr. Nelson’s claim also fails because he cannot show that, had the warning been different, his physicians’ decisions to prescribe Tysabri would have changed. See Strumph v. Schering Corp., 606 A.2d 1140, 1148 (N.J. App. Div. 1992) (Skillman, J. dissenting), rev’d, 626 A.2d 1090 (N.J. 1993) (adopting Skillman dissent).25/ First, there is no affirmative testimony in this case from any of the prescribing physicians that they would have done anything differently had the labeling included information earlier about duration of treatment, prior immunosuppression, and the significance of a positive or negative anti-JCV antibody test (unsupported by data).26/ Second, Drs. Zabad and Citak were unequivocally aware of the PML risk when they prescribed Tysabri and they discussed the risk with Mr. Nelson (SF ¶¶ 82, 93). They testified that the labeling adequately warned of the PML risk to permit them to prescribe the drug safely. (SF ¶¶ 84, 92).27/ They also testified that based on what was known at the time, it was a reasonable 25/ There is no dispute that at the time Dr. Preiningerova treated Mr. Nelson with Tysabri there had only been the three PML cases that lead to Tysabri’s removal from the market, before the first two post-approval cases in July 2008, so there is no colorable claim that Defendants could have said anything in the labeling that would have changed her prescribing decision. 26/ Moreover, there is no evidence that Mr. Nelson ever took immunosuppressant drugs prior to being prescribed Tysabri. Both Dr. Citak and Dr. Zabad testified that Mr. Nelson took Avonex, but they were unaware of any prior use of an immunosuppressant by Mr. Nelson and the record is bereft of any such evidence. (SF ¶¶ 85). 27/ Dr. Citak testified that he had no information that the Tysabri label was incorrect or inaccurate. (SF ¶ 96). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 35 of 49 PageID: 2158 29 medical judgment to prescribe Tysabri to Mr. Nelson. (SF ¶¶ 88, 94). See Baker v. App. Pharms. LLP, No. 09-05725, 2012 U.S. Dist. LEXIS 117970, at *26 (D.N.J. Aug. 21, 2012) (“The Court disagrees that Plaintiffs’ evidence raises a genuine issue of material fact as to the element of proximate cause . . . Dr. Slater stood by his decision to administer heparin to Mrs. Baker.”). Third, Dr. Citak testified that it is not his practice to review a drug’s package insert. (SF ¶ 97). Dr. Citak is familiar with the medication he prescribes, including Tysabri, but his general practice is to obtain information about drugs through medical literature, conferences, and discussions with colleagues, and not drug labeling. (SF ¶ 95). An allegedly inadequate warning cannot be the proximate cause of a plaintiff’s injury where a prescribing physician did not read the drug’s labeling or knew of the alleged risks independently and still prescribed the drug. See Baker, 2012 U.S. Dist. LEXIS 117970, at *27 (no proximate cause because “a different warning would not have made a difference in Mrs. Baker’s treatment or outcome because [the prescribing physician] would not have reviewed it” where prescribing physician testified at deposition that “he does not read the label of drugs he prescribes often.”); Appleby, 2005 U.S. Dist. LEXIS 32875, at *15-18 (summary judgment for defendant on failure to warn claim where “there is every indication that Plaintiff’s doctor, Dr. Krachman, did not read package inserts or listen to drug representatives”); Rossitto, 2016 N.J. Super. Unpub. LEXIS 1714, at *62-63 (the inadequacy of a warning cannot be the proximate cause of an injury where “the physician either did not read the warning, or had independent knowledge of the risks.”). Fourth, Dr. Citak continued to prescribe and administer Tysabri to Mr. Nelson after the labeling was updated to include the duration of use and prior immunosuppression risks. (SF ¶¶ Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 36 of 49 PageID: 2159 30 98, 109).28/ This fact is dispositive of any claim that Dr. Citak would have acted differently had he been warned about these PML risk factors earlier. (Fourth Amend. Compl., Dkt. 142, ¶¶ 52, 61, 63); see McElroy v. Eli Lilly & Co., 495 F. App’x. 166 (2d Cir. 2012) (applying Nebraska law) (summary judgment granted where no causation could be established because physician continued to prescribe drug after manufacturer sent letter to doctors warning of risk); Cooper v. Bristol-Myers Squibb Co., No. 07-cv-885, 2013 U.S. Dist. LEXIS 1768, at *21-22 (D.N.J. Jan. 4, 2013) (applying Alabama law) (summary judgment entered on behalf of manufacturer where doctor continued prescribing drug to plaintiff after learning of new warning); Misouria v. Eli Lilly & Co., 394 F. App’x 825, 827 (2d Cir. 2010); Alston v. Caraco Pharms. Inc., 670 F. Supp. 2d 279, 285-86 (S.D.N.Y. 2009) (applying New York law) (summary judgment for defendant on failure to warn claim because no proximate cause where the “decision by the [p]laintiff’s physicians to not alter their conduct, despite being apprised of the possible risks associated with tramadol, demonstrates that a more stringent warning would have had no practical effect on the physicians’ actions”). Finally, both Drs. Zabad and Citak testified that, without sufficient data supporting the meaning of a particular anti-JCV antibody assay result, they would not be able to use the assay result to inform their prescribing decision. Dr. Citak would not have used an anti-JCV antibody assay unless there was published scientific data establishing the significance of assay findings to the PML risk. (SF ¶ 143). Dr. Zabad testified that consistent, reproducible data is necessary to understand the significance of an antibody test result. (SF ¶ 144).29/ As noted, it is undisputed in 28/ Dr. Zabad testified that she knew about a potential duration risk (SF ¶ 87) and considered that the use of another immunosuppressive medication could elevate the PML risk (SF ¶ 88). 29/ Plaintiff seeks to establish proximate cause by asserting that had his physicians used a JCV antibody assay and told him that he tested positive for the anti-JCV antibodies, he would have refused treatment, even though there was no statistically significant data. Plaintiff cannot Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 37 of 49 PageID: 2160 31 this case that no such data existed at the time Mr. Nelson was taking the drug. As such, Plaintiff cannot meet his burden of proving proximate cause, an essential element of his claim. F. Defendants are Entitled to Summary Judgment on Claims Regarding Anti-JCV Antibodies Because They are Preempted by Federal Law, as Three Courts Have Held on the Identical FDA Record. 1. Plaintiff’s Claims are Preempted Because Defendants Could Not Have Warned About JCV Antibodies and Could Not Have Made an Assay Available Without FDA Approval. The Supremacy Clause of the United States Constitution provides that federal law preempts any state law that conflicts with the exercise of federal power. U.S. CONST. art. vi, cl. 2. The U.S. Food, Drug, and Cosmetics Act, and related federal regulations, do not expressly preempt state tort law, including failure to warn and other product liability claims. Wyeth v. Levine, 555 U.S. 555, 581 (2009). However, when the plaintiff’s liability theory in a particular case is based on an argument that the drug manufacturer had a state tort law duty to do something that could not lawfully be done independently by the drug company under federal law, i.e., without the permission of the FDA, “conflict preemption” applies to bar the state law or claim. See, e.g., Mutual Ins. Co. v. Bartlett, 133 S. Ct. 2466, 2471 (2013). When FDA approves a drug, it approves both the drug and the labeling that accompanies that drug, and manufacturers need to seek FDA approval before making any major changes to the FDA-approved label. Bartlett, 133 S. Ct. at 2471 (citing 21 C.F.R. § 314.70(b)(2)(i)). Certain FDA regulations, however, known as the Changes Being Effected (“CBE”) regulations, create a establish proximate cause on that argument because it is inconsistent with the learned intermediary rule. Plaintiff “must show that adequate warnings would have altered [his] doctors’ decision to prescribe” the drug, Strumph, 606 A.2d at 1148 (Skillman, J. dissenting) (rev’d, 626 A.2d 1090 (N.J. 1993) (adopting Skillman dissent)) not whether the physician would have conveyed a test result to plaintiff, or if plaintiff would have accepted the prescribing decision; see also Christison, 2016 U.S. Dist. LEXIS 110273, at *69 (under the learned intermediary doctrine, a drug manufacturer’s duty is to warn “only the physician prescribing the drug,” and the duty “does not run to the patient.”). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 38 of 49 PageID: 2161 32 regulatory pathway by which drug manufacturers can unilaterally make certain non-major changes to their product labels without prior FDA approval. To qualify for use of this regulatory pathway, the label change must: (1) “reflect newly acquired information”;30/ and (2) accomplish one of five objectives listed in the regulation. 21 C.F.R. § 314.70(c)(6)(iii). In Levine, the Supreme Court held that “conflict” or “impossibility” preemption does not apply where the drug manufacturer had the right under the CBE regulations to unilaterally change the label (without advance FDA permission) to reflect newly available safety information and because Wyeth offered no “clear evidence” that the FDA would have rejected such a proposed change. Levine, 555 U.S. at 568; 21 C.F.R. § 314.70. Two years later, the Supreme Court held in PLIVA v. Mensing that a generic drug manufacturer could not be held liable on a failure to warn claim because only the branded drug company had the legal right to change or propose changes to an FDA-approved label. 564 U.S. 604, 623-25 (2011). More recently, in Bartlett, the Supreme Court held that a drug manufacturer, whether a generic or a brand-name manufacturer, could not be liable for a defect in the design of a product unless the drug company could unilaterally change the design without FDA approval. Bartlett, 133 S.Ct. at 2471. In In re Celexa and Lexapro Mktg. and Sales Practices Litig., 779 F.3d 34, 40 (1st Cir. 2015), the First Circuit held, based on Levine and its progeny, that if the CBE process is not available to the defendant to change the initial FDA-approved labeling (as, for example, when the label change would not be based on “newly-acquired” information), state law failure to warn claims based on alleged inadequacies in the drug’s FDA-approved labeling are preempted. In 30/ FDA defines “newly acquired information” narrowly: Newly acquired information means data, analysis, or other information not previously submitted to the agency, which may include (but are not limited to) data derived from new clinical studies, reports of adverse events, or new analyses of previously submitted data (e.g. meta-analyses) if the studies, events, or analyses reveal risks of a different type or greater severity or frequency that previously included in submissions to FDA. 21 C.F.R. § 314.3(b). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 39 of 49 PageID: 2162 33 other words, a drug company cannot change the initial FDA-approved warnings unless it has both newly acquired information and a legal avenue to change the label through the CBE regulations. As explained by the First Circuit, “the line so drawn lets FDA be the exclusive judge of safety and efficacy based on information available at the time of commencement of marketing, while allowing states to reach a contrary conclusion when new information not considered by FDA develops.” Id. at 41. Here, Plaintiff alleges that during the time his neurologists prescribed Tysabri to him, Defendants had a duty to warn patients that if they have anti-JCV antibodies they are at a higher risk of developing PML (see, e.g., Fourth Amend. Compl. ¶ 85). But Defendants could not lawfully have changed the Tysabri warning label without FDA approval based on adequate data. The CBE regulations do not apply because a drug manufacturer cannot add or change a black box warning without prior Agency approval. 21 C.F.R. § 201.57(c)(i); 44 Fed. Reg. 37434, 37448 (June 26, 1979)(“[T]o ensure the significance of boxed warnings in drug labeling, they are permitted in labeling only when specifically required by FDA.”); Kaleta v. Abbott Labs., 87 F. Supp. 3d 916, 924 (Feb. 2, 2015); see also Jones Expert Report, pp. 15-21, Decl. Ex. 78. (CBEs are not used to modify boxed warnings or to amend REMS programs).31/ Thus, Defendants could not have used the CBE regulations to change Tysabri’s black box warning. In addition, the CBE regulations do not apply to labeling changes based on information that was available to FDA when the drug was approved.32/ See Celexa, 779 F. 3d at 41; FDA, 31/ Similarly, REMS programs like the TOUCH Program are creatures of discretionary Agency action that can only be added or changed on substantive matters with FDA approval. (SF ¶ 48) In this case, FDA made this clear in the marketing approval letter issued in connection with Tysabri’s reintroduction to the market. (SF ¶ 57). 32/ On March 2, 2006, Biogen submitted to FDA an extensive report on the results of antibody testing, conducted at NIH, of available serum samples from Tysabri-treated patients who participated in clinical trials. (SF ¶ 38). The data were inconclusive and the report Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 40 of 49 PageID: 2163 34 CDER, Guidance for Industry: Changes to an Approved NDA or ANDA, 2004 WL 3199016, at *24 (April 2004); Jones Expert Report, pp. 19-21, Decl. Ex. 78. Any change to the labeling or warnings must be based on information discovered, obtained, or as result of a re-analyses of data after the FDA’s approval. Celexa, 779 F. 3d at 41.33/ The record is bereft of any evidence that any such information was available to Defendants during the time Mr. Nelson was taking the drug.34/ On the contrary, the undisputed evidence is that in late 2009, a panel of U.S. regulatory experts determined that “data on the assay was too preliminary to be of predictive value” regarding PML at the time. (SF ¶ 129). In late 2010, FDA expressly rejected such changes to Tysabri’s label. Without sufficient new post-approval data, Biogen could not have used the CBE process to say anything about the significance of anti-JCV antibodies sooner. See also Seufert v. Merck Sharp & Dohme Corp., 187 F.Supp. 3d 1163, 1175 (S.D. Cal. 2016) (stating that any changes to product labeling would have to be supported by reasonable evidence of a causal association, and that it is a technical violation of federal law to propose a CBE that is not based on reasonable evidence). For these reasons, Plaintiff’s claim is preempted under the Supreme Court’s rulings in Bartlett and Mensing and the rationale of the First Circuit in Celexa. concluded that “[c]urrently there is no consensus on a clinically relevant cutoff for the ELISA assay for JCV antibody detection.” (SF ¶ 38). 33/ Major contends that all of the knowledge and techniques necessary to develop an anti- JCV antibody assay (and why in his view such an assay would potentially be significant) were available to Defendants and FDA by 2005. See Ex. 18 to Marino Cert. - Report of Major, at p. 10. 34/ During the time Mr. Nelson was treated with Tysabri there were no statistically significant data concerning the significance of anti-JCV antibodies in relation to PML risk. This fact is undisputed, and Major admitted this fact. (SF ¶¶ 118-119). Nor was there any way to know that the science would develop to the point where an assay could be validated and an assay result could be shown through clinical data to be useful to physicians in making treatment decisions. Plaintiff cannot use the successful results of Defendants’ research efforts to retroactively impose an affirmative duty on Biogen to have warned about those research results earlier. Such a claim disregards the fundamental principle that a drug company’s warning is judged based on the state of scientific knowledge at the time the drug was prescribed. See N.J.S.A § 2A:58C-4; Feldman v. Lederle Lab., 625 A.2d 1066, 1069-70 (N.J. 1993). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 41 of 49 PageID: 2164 35 2. Plaintiff’s Failure to Warn Claims Regarding Anti-JCV Antibodies are Preempted Because There is “Clear Evidence” That FDA Would Not Have Approved Any Such Labeling Changes Before 2012. In Levine, the Supreme Court also held that when a drug manufacturer can show by “clear evidence” that FDA would have rejected a labeling change instituted by the manufacturer under the CBE regulation or otherwise, any state law tort claim based on the failure to make that change is preempted. 555 U.S. at 571-72; see also Dobbs v. Wyeth Pharm., 797 F. Supp. 2d 1264, 1272-77 (W.D. Okla. 2011) (finding the claims preempted due to FDA’s conclusion there was “no scientific evidence to support a causal connection between SSRI’s and suicidality” warranting an enhanced warning”). After Levine, numerous courts have rejected failure to warn claims against prescription drug manufacturers where there is “clear evidence” in the regulatory record that FDA would not have approved a proposed warning.35/ Even under the recent Third Circuit decision, In re Fosamax Alendronate Sodium Prods. Liab. Litig. (“Fosamax”) Defendants have demonstrated in their summary judgment briefing that no reasonable jury could conclude that FDA would have approved a labeling change to warn about the risk of anti-JCV antibodies until January 2012. See Nos. 14-1900 et al., 2017 U.S. App. LEXIS 5075 (3rd Cir. Mar. 22, 2017); see also Amos, No. 13-cv-6375, (W.D.N.Y. Apr. 10, 2017) (holding, on an identical record, that Plaintiff’s claims were preempted). In Fosamax, the Third Circuit held, contrary to other decisions on this issue, that the clear evidence standard is a factual question for the jury. However, the court made it clear, that even 35/ See, e.g., Robinson v. McNeil Consumer Healthcare, 615 F.3d 861, 873 (7th Cir. 2010); Cerveny v. Aventis Inc., 155 F. Supp. 3d 1203, 1218 (D. Utah 2016) (holding “[t]he FDA's denial of the Plaintiffs' theories embodied in [the citizen petition] is clear evidence that the FDA would not have permitted Aventis to strengthen Clomid’s label prior to 1992), aff’d in part and rev’d in part on other grounds by No. 16-4050 (10th Cir. May 2, 2017); In re: Incretin-based Therapies Prods. Liab. Litig., 142 F. Supp. 3d 1108, 1132 (S.D. Cal. 2015); Rheinfrank v. Abbott Labs., Inc., 119 F. Supp. 3d 749 (S.D. Ohio 2015); Kaleta v. Abbott Labs, Inc., 87 F. Supp. 3d 916, 924 (S.D. Ill. 2015) (ruling on motion in limine); Glynn v. Merck Sharp & Dohme Corp. (In re Fosamax Prods. Liab. Litig.), 951 F. Supp. 2d 695, 703 (D.N.J. 2013). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 42 of 49 PageID: 2165 36 under that standard, it is plaintiff’s burden on summary judgment to come forward with evidence demonstrating a material issue of fact on the clear evidence issue. The court stated: By describing the ultimate question as one of fact for the jury, we do not mean to suggest that summary judgment is categorically unavailable to a manufacturer asserting a preemption defense. When there is no genuine issue of material fact— that is, when no reasonable jury applying the clear evidence standard of proof could conclude that the FDA would have approved a label change—the manufacturer will be entitled to judgment as a matter of law. In re Fosamax, Nos. 14-1900 et al., 2017 U.S. App. LEXIS 5075 at *28.36/ Here, “no reasonable jury applying the clear evidence standard of proof could conclude that the FDA would have approved a label change.” First, the present case involves FDA’s express rejection of the precise labeling concept asserted by Plaintiff, providing clear evidence that FDA would not allow such change until January 2012. Next, the undisputed summary judgment record contains two “smoking guns” in which FDA rejected a proposed warning about the presence of anti-JCV antibodies—the precise risk that is the basis of Plaintiff’s claims—and required more data. Finally, the plaintiffs in Fosamax “produced sufficient evidence for a reasonable jury to conclude that the FDA would have approved a properly-worded warning about the risk of thigh fractures.” 2017 U.S. App. LEXIS 5075, *3. By contrast, here, Plaintiff has identified no evidence that sufficient data was available sooner that could have been submitted to FDA and upon which FDA would have approved a labeling change. Thus, Plaintiff does not have sufficient evidence to get to a jury, and the Court must find that Plaintiff’s claims are preempted. The undisputed record in this case shows that FDA explicitly rejected inclusion of antibody testing information in Tysabri’s label both before and after Mr. Nelson had stopped 36/ Courts have found that preemption may be decided even on a motion to dismiss. See, e.g., Utts & Utts v. Bristol-Myers Squibb Co. & Pfizer Inc., No. 1:16-cv-05668-DLC (S.D.N.Y. May 8, 2017) (unpublished) (Ex. Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 43 of 49 PageID: 2166 37 taking Tysabri because of the onset of symptoms suggesting PML. (SF ¶¶ 78, 131, 134). As noted, in September 2010, FDA rejected Biogen’s proposal to add information to the label concerning anti-JCV assay antibodies, finding that the limited information (17 pre-PML samples) available concerning the correlation between a positive antibody finding and PML was not enough data to justify a label change. (SF ¶ 133). FDA also decided that the number of cases was too small, the samples were obtained retrospectively and it was “too early” to support the methodology. (SF ¶ 133).37/ In November 2010, FDA also rejected Biogen’s proposal to make the anti-JCV assay available to physicians based on FDA’s determination that “[t]he usefulness of this test in treatment with Tysabri has not been established.” (SF ¶ 134-136). FDA’s refusal in late 2010 to permit labeling concerning the assay and the significance of JCV antibodies based on the insufficiency of the available data to demonstrate “clinical utility,” is “clear evidence” that FDA would not have permitted a label change earlier, during the time period in which Mr. Nelson was being treated with the drug. In fact, it is conclusive evidence. For this reason, the Christison, Gentile, and Amos courts all held, on the identical FDA regulatory record, that claims challenging the adequacy of the PML warnings based on the failure to discuss antibodies are preempted. In Christison, the court held that FDA would not have approved a change to the Tysabri label regarding JCV antibodies until 2012—more than a year after Mr. Nelson’s PML diagnosis. The court explained: The FDA was aware of the potential link between JCV antibodies and PML as early as 2006, but the FDA did not approve changes to the Tysabri label regarding JCV antibodies until 2012. The Companies are correct that “[i]f 17 Tysabri- association pre-PML samples were insufficient to persuade FDA in 2010 of the 37/ Major acknowledged that the only way to correlate an antibody finding to PML risk was to have a sufficient number of pre-PML blood samples, preferably prospectively obtained (to have a more “robust” finding) (Major Dep. Tr. 418:20-420:8), and that the number of PML cases/samples prior to 2010 was insufficient to draw any conclusions. Indeed, he estimated that it would take about 100 cases to obtain a useful statistical result. Id. Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 44 of 49 PageID: 2167 38 predictive value of antibody testing in connection with PML risk stratification, there clearly would not have been sufficient data more than two years earlier . . . ” Accordingly, there is “clear evidence” that the FDA would not have approved a change to the Tysabri label prior to Mrs. Christison’s death, and the causes of action that Mr. Christison raises in this matter—negligence; negligent failure to warn; and negligent misrepresentation—which are based in state law, are preempted by federal requirements mandating FDA approval of changes to a drug’s warning label. Christison, 2016 U.S. Dist. LEXIS 110273, at *81-82. Similarly, in Gentile, the court held that “FDA’s decision to reject the proposed modifications regarding risks associated with providing Tysabri to patents with the JCV antibody demonstrates that prior to [plaintiff’s] diagnosis, defendants could not have strengthened their warnings to comply with state law without violating the FDA’s decision.” 2016 Mass. Super. LEXIS 238, at *26. Indeed, the court found that “FDA rejected defendants’ proposed change in the warning not because of the language used, but because the supporting data was not yet sufficiently persuasive.” Id. at *27. Finally, in Amos the court held “the evidence of record leads inescapably to the conclusion that the FDA would not have approved a change to Tysabri’s label prior to 2012. . . in this case, there exists not one but two ‘smoking gun’ rejections from FDA. . .the FDA rejected that proposal, stating that it did not believe that there was currently sufficient information to support the clinical utility of testing for JC virus antibodies.” Amos, No. 6:13-cv-06375 (W.D.N.Y. Apr. 10, 2017) (unpublished). The reasoning in Christison, Gentile, and Amos is supported by a number of closely analogous cases where courts have held that failure to warn claims against brand-name prescription drug manufacturers are preempted because of “clear evidence” that FDA would not have approved the labeling change argued by plaintiff, even if it had been unilaterally made by Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 45 of 49 PageID: 2168 39 the drug company through a CBE.38/ See, e.g., Rheinfrank, 119 F. Supp. 3d at 766; Kaleta, 87 F. Supp. 3d at 924 (ruling on motion in limine).39/ Because FDA twice rejected Biogen’s proposed label change regarding the significance of anti-JCV antibodies in 2010, after Mr. Nelson stopped taking Tysabri and did not allow this change until January 2012, there is conclusive evidence that FDA would not have approved the change earlier. The claim is preempted. G. Elan Was Not the License-Holder for Tysabri and Had No Legal Right to Initiate a Labeling Change or To Seek FDA Approval For Such A Change; The Failure To Warn Claims Against Elan Are Also Preempted on That Ground. Elan is entitled to summary judgment on Plaintiff’s warnings claims on the additional independent preemption ground that it was not the holder of the approved Tysabri application 38/ Although “clear evidence” is a fact-specific standard, this body of case law demonstrates a developing bright-line rule regarding “clear evidence” after Levine: a warning change rejected by the FDA for lack of scientific evidence is “clear evidence” that this change would have also been rejected at any earlier date, thus a claim based on the rejected warning is preempted. 39/ The Rheinfrank court’s rationale applies with equal force here: The Court finds that there is clear evidence that the FDA would not have approved a change to the 1999 label to include a warning of developmental delay . . . . Abbott tried, on various occasions, to secure approval of a developmental delay warning and its requests were twice denied by the FDA. In light of the fact that the FDA rejected the developmental delay warning in 2006 because it did not find that the available scientific evidence at that time supported the addition of such a warning, it is highly unlikely that the available scientific evidence, seven years prior to that date in 1999, would have supported the addition of such a warning. Notably, the FDA did not actually approve this developmental delay language until 2011. 119 F. Supp. 3d at 766-67 (citation omitted); see also In re: Byetta Cases, No. JCCP 4574, (Ca. Sup. Ct. Nov. 13, 2015); Robinson v. McNeil Consumer Healthcare, 615 F.3d 861, 873 (7th Cir. 2010); Cerveny, 155 F. Supp. 3d at 1216-1218 (holding “[t]he FDA’s denial of the Plaintiffs’ theories embodied in [the citizen petition] is clear evidence that the FDA would not have permitted Aventis to strengthen Clomid’s label prior to 1992), aff’d in part and rev’d in part on other grounds by No. 16-4050 (10th Cir. May 2, 2017); Seufert, 187 F. Supp. 3d at 1165, 1174- 76; In re: Incretin-based Therapies Prods. Liab. Litig., 142 F. Supp. 3d at 1132; In re Fosamax, MDL No. 2243, 2014 U.S. Dist. LEXIS 42253, at *56-57 (D.N.J. March 26, 2014). Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 46 of 49 PageID: 2169 40 and thus had no legal authority or ability to unilaterally change the Tysabri labeling. (SF ¶5). Under federal law, “[a] brand-name manufacturer seeking new drug approval is responsible for the accuracy and adequacy of its label.” Mensing, 564 U.S. at 613 (citing 21 U.S.C. §§ 355(b)(1), (d)); Levine, 555 U.S. at 570-71. Federal regulations state that “the holder of an approved application” may make changes to “add or strengthen a contraindication, warning, precaution, or adverse reaction for which the evidence of a causal association satisfies the standard for inclusion in the labeling under 201.57(c) of this chapter.” 21 C.F.R. § 314.70(c)(6)(iii)(A) (2006) (emphasis added). Biogen is the holder of the approved application for Tysabri in the United States and is responsible by law and by its agreement with Elan for pharmacovigilance activities in the United States and Elan acts as the distributor. (SF ¶5). Because Elan is not the “holder of an approved application” (the NDA), Elan cannot unilaterally effect any changes to Tysabri’s label. To paraphrase one Court’s explanation of the rule, “a contractual relationship between [Biogen and Elan] cannot change the fact that [Elan] is not the NDA holder.” In re Fosamax Prods. Liab. Litig., No. 3:08-cv-00008, 2012 U.S. Dist. LEXIS 5817, at *26-28 (D.N.J. Jan. 17, 2012); see Brazil v. Janssen Research and Develop. LLC, 196 F. Supp. 3d 1351, 1364-65 (N.D. Ga. 2016) (dismissing plaintiff’s claims premised on a failure to warn against a defendant that did not hold the NDA because “[w]hen a company does not have the NDA, it has ‘no more power to change the label’ of a drug than a generic manufacturer.”) (quoting In re Darvocet, Darvon, & Propoxyphene Prods. Liab. Litig., 756 F.3d 917, 940 (6th Cir. 2014)). Because Elan could not “independently do under federal law what [Plaintiff claims] state law requires of it,” the state law failure to warn claims brought against Elan are preempted. Mensing, 564 U.S. at 620; see Brazil, 196 F. Supp. 3d at 1364-65 (same). The Gentile and Amos courts granted summary judgment as Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 47 of 49 PageID: 2170 41 to Elan for this reason as well. Gentile, 2016 Mass. Super. LEXIS 238, at *28 (“Biogen is the holder of the original, approved application for Tysabri. Consequently, Elan could not have sought modifications of the label.”); Amos, No. 6:13-cv-06375 (W.D.N.Y. Apr. 10, 2017) (“Federal regulations do not permit Elan, as a distributor, to change labeling. Any claim that state law compelled it to do so is therefore preempted.”). IV. CONCLUSION For all of the foregoing reasons, Defendants are entitled under Fed. R. Civ. P. 56 to the entry of final judgment in their favor and respectfully request that the Court enter summary judgment in Defendants’ favor on Plaintiff’s claim with prejudice, and grant Defendants any other relief that the Court deems just and proper. Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 48 of 49 PageID: 2171 42 Respectfully submitted, BIOGEN INC. ELAN PHARMACEUTICALS, LLC, By their attorneys, Kevin H. Marino John D. Tortorella MARINO, TORTORELLA & BOYLE, P.C. 437 Southern Boulevard Chatham, New Jersey 07928-1488 Tel: (973) 824-9300 Fax: (973) 824-8425 Joseph G. Blute (admitted pro hac vice) jblute@mintz.com Yalonda T. Howze (admitted pro hac vice) ythowze@mintz.com MINTZ LEVIN COHN FERRIS GLOVSKY & POPEO, P.C. One Financial Center Boston, MA 02111 Telephone: (617) 542-6000 Fax: (617) 542-2241 Case 2:12-cv-07317-JMV-MF Document 154-1 Filed 05/15/17 Page 49 of 49 PageID: 2172 Kevin H. Marino John D. Tortorella MARINO, TORTORELLA & BOYLE, P.C. 437 Southern Boulevard Chatham, New Jersey 07928-1488 Telephone: (973) 824-9300 Fax: (973) 824-8425 e-mail: kmarino@khmarino.com OF COUNSEL: Joseph G. Blute (admitted pro hac vice) Yalonda T. Howze (admitted pro hac vice) MINTZ, LEVIN, COHN, FERRIS, GLOVSKY AND POPEO, P.C. One Financial Center Boston, Massachusetts 02111 Tel: (617) 542-6000 Fax: (617) 542-2241 e-mail: jgblute@mintz.com Attorneys for Defendants Biogen Inc. & Elan Pharmaceuticals, LLC UNITED STATES DISTRICT COURT DISTRICT OF NEW JERSEY ANDREW NELSON, Plaintiff, v. BIOGEN INC. AND ELAN PHARMACEUTICALS, LLC, Defendants. Hon. John M. Vazquez, U.S.D.J. No. 2:12-cv-7317-JMV-MF LOCAL RULE 56.1 STATEMENT OF MATERIAL FACTS NOT IN DISPUTE Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 1 of 41 PageID: 2173 - i - TABLE OF CONTENTS I. THE PARTIES.....................................................................................................................1 II. INTRODUCTION ...............................................................................................................2 III. MULTIPLE SCLEROSIS (“MS”).......................................................................................6 IV. TYSABRI® .........................................................................................................................7 A. Tysabri’s Approval and Subsequent Withdraw from the Market ............................7 B. Defendants Voluntarily Withdraw Tysabri From the Market..................................8 C. Tysabri is Reapproved with a Black Box Warning and an FDA-Mandated Risk Evaluation and Management Strategy (“REMS”) Program. .........................11 V. MR. NELSON’S MULTIPLE SCLEROSIS TREATMENT............................................16 VI. MR. NELSON’S TYSABRI TREATMENT AND PML DIAGNOSIS ...........................20 VII. DEFENDANTS’ PHARMACOVIGILANCE IN THE POST-MARKETING PERIOD IDENTIFIED THREE PML RISK FACTORS..................................................23 VIII. MATERIAL FACTS REGARDING THE JCV ANTIBODY ASSAY............................26 IX. DR. CITAK TESTIFIED TO THE LIMITED UTILITY OF THE ANTI-JCV ANTIBODY ASSAY WHILE HE WAS TREATING MR. NELSON ............................36 X. EXPERT TESTIMONY ....................................................................................................36 XI. COURTS HAVE FOUND UNDISPUTED FACTS ON THE SAME FDA REGULATORY FILE IN RELATED CASES .................................................................38 Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 2 of 41 PageID: 2174 Defendants Biogen Inc. (“Biogen”) and Elan Pharmaceuticals, LLC (“Elan”) respectfully submit the following Local Rule 56.1 Statement of Material Facts Not in Dispute in Support of their Motion for Summary Judgment. True and accurate copies of the deposition transcripts, exhibits, pleadings, and other material relied upon below to support this Statement of Facts are attached to the Certification of Kevin Marino (“Marino Cert.”). Citations to the Marino Certification are referenced herein as “Ex. # to Marino Cert. - [description of the exhibit].” I. THE PARTIES 1. Plaintiff Andrew Nelson (“Plaintiff or “Mr. Nelson”) resides at 3304 Autumn Drive, Tinton Falls, NJ 07753. (Ex. 1 to Marino Cert. - Fourth Amended Complaint (“Complaint”), Dkt. No. 142, at ¶ 3.) 2. Defendant Biogen Inc. f/k/a Biogen Idec Inc. (“Biogen”) is a Delaware corporation with a principal place of business at 225 Binney Street, Cambridge, MA 02142. (See Biogen Contact Information available at https://www.biogen.com/en_us/about- biogen/contact.html (last visited May 12, 2017).) 3. Defendant Elan Pharmaceuticals, LLC (“Elan”) is a wholly owned subsidiary of Athena Neurosciences, LLC. Athena Neurosciences, LLC is a wholly owned subsidiary of Elan Holdings Limited. Elan Holdings Limited is a wholly owned subsidiary of Elan Corporation Limited. Elan Corporation Limited is a wholly owned subsidiary of Perrigo Company plc, an Irish public limited company. (Ex. 2 to Marino Cert. - Defendant Elan Pharmaceuticals LLC’s Supplemental Corporate Disclosures, Dkt. No. 83.) 4. For the relevant time period, Elan was a corporation organized under the laws of the State of Delaware with a principal place of business at 800 Gateway Boulevard, South San Francisco, CA, 94080. (Ex. 98 to Marino Cert. - Defendant Elan’s Answer to Third Complaint and Jury Demand, Dkt. No. 55 at ¶ 5.) Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 3 of 41 PageID: 2175 - 2 - 5. Biogen and Elan collaborated on aspects of the research, development and commercialization of Tysabri (natalizumab). Biogen manufactured the drug, held the FDA license, and had regulatory responsibility for the drug in the United States, and was principally responsible for marketing the drug for multiple sclerosis (“MS”) in the United States. Elan distributed the drug in the United States and also had principal responsibility for the marketing of Tysabri for Crohn’s disease, another approved indication for the drug. Elan was also the license holder for the drug in Europe. (Ex. 66 to Marino Cert. - August 15, 2000 Antegren Development and Marketing Collaboration Agreement Between Biogen, Inc. and Elan Pharma International Limited.) II. INTRODUCTION 6. Andrew Nelson was diagnosed with MS in October 2002. (Ex. 1 to Marino Cert. - Complaint at ¶ 54.) 7. Mr. Nelson was first prescribed Tysabri by Dr. Jana Preiningerova in April 2008. (Ex. 43 to Marino Cert. - 4/10/2008 Yale Neurology Clinic Note.) 8. Mr. Nelson’s first Tysabri infusion occurred in May 2008. (Ex. 32 to Marino Cert. - Andrew Nelson TOUCH form (“Nelson TOUCH form(s)”) at BIOGEN-NELSON0000053.) 9. In July 2008, Mr. Nelson relocated to Omaha, Nebraska, and continued Tysabri infusions. Mr. Nelson began seeing Dr. Rana Zabad and continued under her care until August 2009. (Ex. 32 to Marino Cert. - Nelson TOUCH forms.) 10. In September 2009, Dr. Kenneth Citak became Mr. Nelson’s physician with regard to his MS treatment. (Ex. 45 to Marino Cert. - 9/10/2009 Citak Office Note.) 11. Dr. Citak prescribed Mr. Nelson a 300 mg IV infusion of Tysabri every 4 weeks. (Ex. 46 to Marino Cert. - 9/10/2009 Citak Tysabri Prescription.) Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 4 of 41 PageID: 2176 - 3 - 12. Since 2006, the prescribing information for Tysabri has contained a “black box” warning, the strongest warning required or permitted by FDA, concerning the risk of progressive multifocal leukoencephalopathy (“PML”). (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000012; Ex. 16 to Marino Cert. - Expert Report of Dr. Judith Jones (“Jones Report”) at p. 16; Ex. 99 to Marino Cert. - Expert Report of Dr. Joseph Berger (“Berger Report”) at p. 6; see also 21 C.F.R. § 201.57(c)(1); 44 Fed. Reg. 37434, 37448 (FDA June 26, 1979) (“To ensure the significance of boxed warnings in drug labeling, they are permitted in labeling only when specifically required by FDA.”); Ex. 4 to Marino Cert. - January 2008 Tysabri Label at p. 2; Ex. 5 to Marino Cert. - August 2008 Tysabri Label at p. 2; Ex. 6 to Marino Cert. - November 2009 Tysabri Label at p. 2; Ex. 7 to Marino Cert. - July 2010 Tysabri Label at p. 2.) 13. As stated in FDA’s Guidance regarding Content and Format of Labeling: A boxed warning is ordinarily used to highlight for prescribers one of the following situations:  There is an adverse reaction so serious in proportion to the potential benefit from the drug (e.g., a fatal, life-threatening or permanently disabling adverse reaction) that it is essential that it be considered in assessing the risks and benefits of using the drug OR  There is a serious adverse reaction that can be prevented or reduced in frequency or severity by appropriate use of the drug (e.g., patient selection, careful monitoring, avoiding certain concomitant therapy, addition of another drug or managing patients in a specific manner, avoiding use in a specific clinical situation) OR  FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted (e.g., under 21 CFR 314.520 and 601.42 “Approval with restrictions to assure safe use” or under 505-1(f)(3) of the Federal Food, Drug, and Cosmetic Act (FDCA) “Risk Evaluation and Mitigation Strategies” Elements to assure safe use). (Ex. 16 to Marino Cert. - Jones Report at pp. 16-17; Ex. 13 to Marino Cert. - October 2011 Guidance for Industry on Warnings and Precautions, Contraindications, and Boxed Warning Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 5 of 41 PageID: 2177 - 4 - Sections of Labeling for Human Prescription Drug and Biological Products – Content and Format at p. 11 (by US Department of Health and Human Services).) 14. Throughout the time Mr. Nelson received Tysabri from April 2008 to September 2010, the Tysabri label included a “black box” warning concerning the risk of PML. The label in effect in April 2008 contained the following black box warning: WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY TYSABRI® increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Although the cases of PML were limited to patients with recent or concomitant exposure to immunomodulators or immunosuppressants, there were too few cases to rule out the possibility that PML may occur with TYSABRI monotherapy [see Warnings and Precautions (5.1)].  Because of the risk of PML, TYSABRI is available only through a special restricted distribution program called the TOUCHTM Prescribing Program. Under the TOUCHTM Prescribing Program, only prescribers, infusion centers, and pharmacies associated with infusion centers registered with the program are able to prescribe, distribute, or infuse the product. In addition, TYSABRI must be administered only to patients who are enrolled in and meet all the conditions of the TOUCHTM Prescribing Program [see Warnings and Precautions (5.1, 5.2)].  Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom that may be suggestive of PML. TYSABRI dosing should be withheld immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation that includes a gadolinium-enhanced magnetic resonance imaging (MRI) scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended [see Contraindications (4), Warnings and Precautions (5.1).]. 1/ 1/ In the July 2010 Tysabri label, the final label in effect while Mr. Nelson was prescribed and infused with Tysabri, the language of this paragraph read: TYSABRI® increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Cases of PML have been reported in patients taking TYSABRI who were recently or concomitantly treated with immunomodulators or immunosuppressants, as well as in patients receiving TYSABRI as monotherapy [see Warnings and Precautions (5.1)]. (Ex. 7 to Marino Cert. - July 2010 Tysabri Label at p. 2.) Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 6 of 41 PageID: 2178 - 5 - (Ex. 4 to Marino Cert. - January 2008 Tysabri Label at p. 2; Ex. 7 to Marino Cert. - July 2010 Tysabri Label at p. 2.) 15. In accordance with the TOUCH program requirements, on April 10, 2008, Mr. Nelson signed and initialed a TOUCH enrollment form, which included the following statement: I acknowledge that: . . . TYSABRI increases your chance of getting a rare brain infection that usually causes death or severe disability.  This infection is called progressive multifocal leukoencephalopathy (PML). PML usually happens in people with weakened immune systems  No one can predict who will get PML. There is no known treatment, prevention, or cure for PML  My chance for getting PML may be higher if I am also being treated with other medicines that can weaken my immune system, including other MS treatments  Even if I use TYSABRI alone to treat my MS, it is not known if my chance for getting PML will be lower. It is also not known if treatment for a long period of time with TYSABRI can increase my chance for PML  I should call my doctor right away if I get any new or worsening symptoms that last several days especially nervous system symptoms. Some of these symptoms include a new or sudden change in my thinking, eyesight, balance, or strength, but I should also report other new or worsening symptoms. (Ex. 31 to Marino Cert. - Nelson TOUCH Enrollment Form at p. 2; Ex. 16 to Marino Cert. - Jones Report at p. 48; Ex. 9 to Marino Cert. - Andrew Nelson Deposition Transcript (“Nelson Dep. Tr.”) at 66:24-67:3, 71:22-76:18.) 16. In accordance with the TOUCH program requirements, Mr. Nelson acknowledged to a specially trained infusion nurse that he had reviewed the Tysabri Medication Guide Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 7 of 41 PageID: 2179 - 6 - concerning the PML risk at each of his 26 monthly Tysabri infusions through September 2010. (Ex. 32 to Marino Cert. - Nelson TOUCH Forms.) 17. Andrew Nelson was diagnosed with PML in December 2010. (Ex. 1 to Marino Cert. - Complaint at ¶ 65.) 18. After stopping Tysabri Mr. Nelson stated that Tysabri is “the best of the best drugs, but I would caution anyone to take the risks seriously. I did not because I thought I would never be the one to develop PML. Turns out I was.” (Ex. 9 to Marino Cert. - Nelson Dep. Tr. at 127:15-128:12; Ex. 50 to Marino Cert. - 6/20/2012 Nelson Email.) III. MULTIPLE SCLEROSIS (“MS”) 19. MS is a chronic, progressive, and disabling autoimmune disease of the central nervous system (“CNS”) (the brain, spinal cord, and optic nerves). In MS, white blood cells enter the CNS and attack myelin, a fatty substance that surrounds nerve fibers. Myelin assists the nerves in efficiently transmitting the signals to and from the brain that control all functions of the body. (Ex. 99 to Marino Cert. - Berger Report at p. 5; Ex. 24 to Marino Cert. - Inglese M. Multiple sclerosis: new insights and trends. AJNR Am J Neuroradiol 2006; 27(5):954-957.) 20. MS causes gradual destruction of the myelin (“demylination”), and resulting nerve damage throughout the brain and spinal cord leaves scar tissue called “scleroses,” which can be seen on magnetic resonance imaging (“MRI”) images. Depending on where in the CNS the damage occurs, the demyelination can result in a broad range of MS symptoms including loss of muscle control, trouble walking, blurred vision or blindness, incontinence, and fatigue. (Ex. 99 to Marino Cert. - Berger Report at p. 5; Ex. 22 to Marino Cert. - Frohman TC, Castro W, Shah A, et al. Symptomatic therapy in multiple sclerosis. Therapeutic Advances in Neurological Disorders. 2011;4(2):83-98.) Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 8 of 41 PageID: 2180 - 7 - 21. The damage caused by MS can lead to brain atrophy and cognitive impairment. In severe cases, MS sufferers can be confined to a wheelchair or be bedridden. The life expectancy of an MS patient can be shortened. (Ex. 10 to Marino Cert. - Dr. Kenneth Citak Deposition Transcript (“Citak Dep. Tr.”) at 58:1-60:5; Ex. 11 to Marino Cert. - Dr. Rana Zabad Deposition Transcript (“Zabad Dep. Tr.”) at 68:1-19.) 22. The most common type of MS is “relapsing-remitting MS,” where there are specific attacks, followed by remission. Another form of MS is called “secondary progressive MS,” which is characterized by a continued worsening of the disease without identifiable periods of remission. (Ex. 99 to Marin Cert. - Berger Report at p. 5; Ex. 10 to Marino Cert. - Citak Dep. Tr. at 53:24-54:12.) 23. MS has no known cure, and until 1993, there were no disease modifying medications available to treat the disease. While treatment options have been growing in number over the past two decades, the therapeutic options do not work in all cases or can lose their therapeutic impact over time. All MS treatments have side effects that can impact a patient’s ability to use or tolerate the medication. (Ex. 99 to Marino Cert. - Berger Report at p. 5; Ex. 10 to Marino Cert. - Citak Dep. Tr. at 55:20-23, 60:21-61:5.) IV. TYSABRI® A. Tysabri’s Approval and Subsequent Withdraw from the Market 24. Tysabri (natalizumab) is a recombinant, humanized, monoclonal antibody that inhibits the trafficking of inflammatory white blood cells into the CNS, and thereby protects the myelin from attack and resulting nerve cell damage. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000012; Ex. 99 to Marino Cert. - Berger Report at p. 6; Ex. 27 Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 9 of 41 PageID: 2181 - 8 - to Marino Cert. - Rudick R, Sandrock A. Natalizumab: α4-integrin antagonist selective adhesion molecule inhibitors for MS. Expert Rev. Neurotherapeutics 2004 4(4), 571-580.) 25. Tysabri decreases the number of MS relapses, and reduces and delays nerve damage and resulting disability. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000015; Ex. 99 to Marino Cert. - Berger Report at p. 6; Ex. 16 to Marino Cert. - Jones Report at p. 27.) 26. Data from the Tysabri clinical trials demonstrated 67% reduction in annual relapses, a 42% reduction in disability progression, and an 83% reduction in new lesions (as seen on MRI) in Tysabri versus those on placebo. Tysabri continues to be highly efficacious in treating MS and remains an important treatment option prescribed by specialists for thousands of patients worldwide. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000015; Ex. 16 to Marino Cert. - Jones Report at p. 29; Ex. 99 to Marino Cert. - Berger Report at p. 8; Ex. 25 to Marino Cert. - Polman C, O’Connor P, Havrdova, E, Hutchinson, M, et al. A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis, N. Engl. J. Med. 2006 March 354:9: 899-910.) 27. FDA first approved Tysabri in November 2004 for treatment of relapsing forms of MS. (Ex. 55 to Marino Cert. - November 23, 2004 FDA Approval Letter for Tysabri (“November 23, 2004 Approval Letter”); Ex. 16 to Marino Cert. - Jones Report at p. 29.) 28. Biogen is FDA’s license holder for Tysabri. (Ex. 55 to Marino Cert. - November 23, 2004 Approval Letter.) B. Defendants Voluntarily Withdraw Tysabri From the Market 29. In February 2005, Defendants received reports that two patients in ongoing clinical trials of Tysabri used in combination with Avonex (another MS medication) developed Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 10 of 41 PageID: 2182 - 9 - PML. These patients were treated with Tysabri in combination with Avonex for a median of 120 weeks. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000018; Ex. 16 to Marino Cert. - Jones Report at p. 31; Ex. 51 to Marino Cert. - February 28, 2005 FDA News Release.) 30. PML had never been associated with MS, Avonex, or Tysabri prior to February 2005. PML was typically associated with AIDS and organ transplant patients. (Ex. 99 to Marino Cert. - Berger Report at p. 2; Ex. 16 to Marino Cert. - Jones Report at p. 28.) 31. PML is a rare viral brain infection that is caused by the JC virus. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000018; Ex. 99 to Marino Cert. - Berger Report at p. 2.) 32. The JC virus is usually harmless, ubiquitous, and is carried by the majority of adults. (Ex. 99 to Marino Cert. - Berger Report at p. 2; Ex. 12 to Marino Cert. - Deposition of Dr. Eugene Major (“Major. Dep. Tr.”) at 377:19-378:6, 493:22-494:25; Ex. 21 to Marino Cert. - Eugene O. Major, Human Polyomavirus, in Fields Virology 2175, 2176 (Knipe et al. eds., 4th ed. 2001.) 33. During nearly the entire period in which Mr. Nelson was prescribed Tysabri, until Biogen’s research was published in September 2010 in the Gorelik Annals of Neurology paper, it was generally accepted in the scientific community that upwards of 80% of adults had been exposed to the JC virus. (Ex. 12 to Marino Cert. - Major. Dep. Tr. at 377:19-378:6, 493:22- 494:25; Ex. 29 to Marino Cert. - Stolt A, Sasnauskas K, Koskela P, Lehtinen M, Dillner J. Seroepidemiology of the human polyomaviruses. J Gen Virol 2003 June;84(Pt 6):1499-504; Ex. 26 to Marino Cert. - Rollison DE, Helzlsouer KJ, Alberg AJ, Hoffman S, Hou J, Daniel R et al. Serum antibodies to JC virus, BK virus, simian virus 40, and the risk of incident adult astrocytic Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 11 of 41 PageID: 2183 - 10 - brain tumors. Cancer Epidemiol Biomarkers Prev 2003 May;12(5):460-3; Ex. 30 to Marino Cert. - Stuve O, Marra CM, Cravens PD, Singh MP, Hu W, Lovett-Racke A et al. Potential risk of progressive multifocal leukoencephalopathy with natalizumab therapy: possible interventions. Arch Neurol 2007 February;64(2):169-76; Ex. 21 to Marino Cert. - Eugene O. Major, Human Polyomavirus, in Fields Virology 2175, 2176 (Knipe et al. eds., 4th ed. 2001).) 34. On February 28, 2005, after learning of two confirmed cases of PML associated with Tysabri use, Biogen voluntarily withdrew Tysabri from the market, suspended its use in clinical trials, and began a review of the data to evaluate the PML risk and research whether there was any way to stratify the PML risk (i.e., identity individual risk factors for PML that physician could use in make prescribing decision and counseling patients.). (Ex. 64 to Marino Cert. - February 28, 2005 Dear Healthcare Professional Letter; Ex. 51 to Marino Cert. - February 28, 2005 FDA News Release; Ex. 52 to Marino Cert. - March 1, 2005 FDA Public Health Advisory; Ex. 16 to Marino Cert. - Jones Report at p. 31.) 35. After Biogen’s voluntary withdrawal of Tysabri, Biogen and Elan worked with experts on PML and MS to analyze the PML cases and to better understand and quantify the risk. (Ex. 16 to Marino Cert. - Jones Report p. 31; Ex. 68 to Marino Cert. - Key Take-aways from March 4 PML Expert Panel Meeting; Ex. 56 to Marino Cert. - March 4, 2005 “TYSABRI Safety Update” at ELAN_TC_00058217-220; Ex. 69 to Marino Cert. - March 7 & 8, 2006 Peripheral and Central Nervous System Drugs Advisory Committee Meeting Minutes.) 36. In April 2005, Biogen announced its safety evaluation of Tysabri had led to the discovery of a third case of PML in a patient from a clinical trial in Belgium for the use of Tysabri in Crohn’s Disease. This Crohn’s disease patient was treated with Tysabri for eight months and had a history of immunosuppressant drug use. He had originally been misdiagnosed Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 12 of 41 PageID: 2184 - 11 - with a brain tumor. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000018; Ex. 16 to Marino Cert. - Jones Report at p. 31; Ex. 65 to Marino Cert. - April 2005 Dear Healthcare Professional Letter.) C. Tysabri is Reapproved with a Black Box Warning and an FDA-Mandated Risk Evaluation and Management Strategy (“REMS”) Program. 37. In evaluating Tysabri prior to its return to the market in 2006, FDA requested that Biogen conduct an assessment for the presence of JCV antibody at baseline for patients entering clinical trials. (Ex. 75 to Marino Cert. - November 18, 2005 Letter from Rusell Katz, M.D., FDA to Nadine Cohen, Biogen.) 38. On March 2, 2006, Biogen submitted to FDA a report on the results of antibody testing conducted at a laboratory at the National Institute of Health (“NIH”) – a laboratory led by Plaintiff’s expert Dr. Eugene Major, Ph.D. – of available serum samples from Tysabri treated patients who participated in clinical trials. The report concluded “[c]urrently there is no consensus on a clinically relevant cut off for the ELISA assay or JCV antibody detection.” (Ex. 57 to Marino Cert. - March 2, 2006 sBLA Amendment Submission to FDA; Ex. 68 to Marino Cert. - Key Take-aways from March 4 PML Expert Panel Meeting; Ex. 17 to Marino Cert. - Expert Report of Dr. Raphael Viscidi (“Viscidi Report”) at pp. 3-5, 8-9; Ex. 12 to Marino Cert. - - Major Dep. Tr. at 358:11 – 360:25.) 39. On March 7 and 8, 2006, an FDA Advisory Panel convened to consider Biogen’s proposal to permit Tysabri back on the market for treatment of relapsing forms of MS with new labeling concerning the PML risk. (Ex. 16 to Marino Cert. - Jones Report at p. 36; Ex. 67 to Marino Cert. - February 16, 2006 Meeting Materials for Peripheral and Central Nervous System Drugs Advisory Committee; Ex. 69 to Marino Cert. - March 7 & 8, 2006 Peripheral and Central Nervous System Drugs Advisory Committee Meeting Minutes.) Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 13 of 41 PageID: 2185 - 12 - 40. The FDA Advisory Panel recommended FDA re-approve Tysabri after the Advisory Panel reviewed the benefit and risk data, and held a public hearing at which the Advisory Panel heard testimony that Tysabri should be approved and returned to the market from MS specialists, patient advocacy groups, and patients who had been treated with Tysabri in clinical trials. (Ex. 16 to Marino Cert. - Jones Report at pp. 34-37; Ex. 69 to Marino Cert. - March 7 & 8, 2006 Peripheral and Central Nervous System Drugs Advisory Committee Meeting Minutes.) 41. On June 5, 2006, FDA reapproved Tysabri’s return to the market as a monotherapy for relapsing forms of MS, subject to a number of new conditions and requirements concerning the PML risk. (Ex. 78 to Marino Cert. - June 5, 2006 Letter from Russell Katz, M.D., of FDA to Nadine D. Cohen, Biogen (“June 5, 2006 Re-approval Letter”); Ex. 16 to Marino Cert. - Jones Report at p. 37.) 42. JCV antibody testing was not required by FDA as a condition of re-approval or as a subject discussed in the label. The Tysabri label presumes that all Tysabri patients are JCV positive or could become infected with the JC virus (Ex. 16 to Marino Cert. - Jones Report at pp. 37, 76; Ex. 78 to Marino Cert. - June 5, 2006 Re-approval Letter; Ex. 3 to Marino Cert. - May 22, 2006 Tysabri label.) 43. As a condition of Tysabri’s re-approval, FDA required that the prescribing information include a “black box” warning informing prescribers that Tysabri use increases the risk of PML along with other warnings concerning the PML risk. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000012; Ex. 78 to Marino Cert. - June 5, 2006 Re- approval Letter.) Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 14 of 41 PageID: 2186 - 13 - 44. A black box warning is a warning printed inside a black box on the first page of drug labeling. (Ex. 16 to Marino Cert. - Jones Report at pp. 16, 20-21; Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000012.) 45. As a condition of re-approval, FDA required in the Tysabri prescribing information a “Warnings” section that stated the following regarding the PML risk: Progressive multifocal leukoencephalopathy, an opportunistic infection caused by the JC virus that typically occurs in patients that are immunocompromised, has occurred in 3 patients who received TYSABRI® in clinical trials (see BOXED WARNING). Two cases of PML were observed in 1869 patients with multiple sclerosis treated for a median of 120 weeks. The third case occurred among 1043 patients with Crohn's disease after the patient received 8 doses. The absolute risk for PML in patients treated with TYSABRI® cannot be precisely estimated, and factors that might increase an individual patient's risk for PML have not been identified. There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs. It is not known whether early detection of PML and discontinuation of TYSABRI® will mitigate the disease. There is limited experience beyond 2 years of treatment. The relationship between the risk of PML and the duration of treatment is unknown. All three cases of PML occurred in patients who were concomitantly exposed to immunomodulators (interferon beta in the patients with multiple sclerosis) or were immunocompromised due to recent treatment with immunosuppressants (e.g., azathioprine in the patient with Crohn's disease). Ordinarily, therefore, patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not be treated with TYSABRI®. However, the number of cases is too few and the number of patients treated too small to reliably conclude that the risk of PML is lower in patients treated with TYSABRI® alone than in patients who are receiving other drugs that decrease immune function or who are otherwise immunocompromised. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000018 (emphasis in original).) 46. The prescribing information also contained the following “Indications and Usage” section: Because TYSABRI® increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability (see BOXED WARNING AND WARNINGS, Progressive Multifocal Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 15 of 41 PageID: 2187 - 14 - Leukoencephalopathy), TYSABRI® is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, alternate multiple sclerosis therapies. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000017 (emphasis in original).) 47. As a condition of re-approval, FDA required that a Medication Guide be provided to physicians and specially trained infusion nurses. The substance of the Medication Guide is printed verbatim in the Tysabri label. Further, only TOUCH certified prescribers could prescribe Tysabri. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri label at BIIB_LABEL_000029-34; Ex. 16 to Marino Cert. - Jones Report at p. 48.) 48. As a condition of re-approval, FDA also mandated that Tysabri only be prescribed in accordance with a mandatory “Risk Evaluation and Management Strategy,” (or “REMS program”), known as the TOUCH Program (“Tysabri Outreach: Unified Commitment to Health”). In its re-approval letter, FDA ordered: “Any change to the [TOUCH] program must be discussed with FDA prior to its institution and is subject to FDA’s determination that the required components are still present.” (Ex. 78 to Marino Cert. - June 5, 2006 Re-approval Letter; Ex. 16 to Marino Cert. - Jones Report at pp. 17-19, 46.) 49. As part of the TOUCH program the Tysabri Medication Guide is provided to patients prior to enrolling in the TOUCH program. When Mr. Nelson enrolled in the TOUCH program this Medication Guide stated the following: What is the most important information I should know about TYSABRI®?  TYSABRI® increases your chance of getting a rare brain infection that usually causes death or severe disability. This infection is called progressive multifocal leukoencephalopathy (PML). PML usually happens in people with weakened immune systems. Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 16 of 41 PageID: 2188 - 15 -  No one can predict who will get PML.  There is no known treatment, prevention, or cure for PML. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000029-34 (emphasis in original); Ex. 16 to Marino Cert. - Jones Report at p. 48; see Ex. 31 to Marino Cert. - Nelson TOUCH Enrollment Form.) 50. FDA re-approved Tysabri in June 2006 “under the provisions of 21 CFR 601.42 (Subpart E) . . . for use as recommended in the agreed upon labeling text, required patient labeling, and the components of the TOUCH™ Risk Minimization Action Plan (RiskMAP).” (Ex. 78 to Marino Cert. - June 5, 2006 Re-approval Letter.) 51. Under § 505-1 of the FDA Amendments Act of 2007, which ensure that the benefits of a drug or biological product outweigh its risks, the TOUCH RiskMAP became a REMS program. (Ex. 16 to Marino Cert. - Jones Report at pp. 17-19; see also Approved Risk Evaluation and Mitigation Strategies (REMS), available at: http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm (last visited May 12, 2017); see also 21 U.S.C. § 355-1 (2011).) 52. In the June 5, 2006, re-approval letter FDA stated that the goals of the TOUCH program were: “to assess the risk of progressive multifocal leukoencephalopathy (PML) associated with Natalizumab (TYSABRI®), minimize the risk of PML, minimize death and disability due to PML, and promote informed risk-benefit decisions regarding TYSABRI' [sic] use.” (Ex. 78 to Marino Cert. - June 5, 2006 Re-approval Letter; Ex. 16 to Marino Cert. - Jones Report at pp. 17-19, 46.) 53. The TOUCH program requires that prior to prescribing Tysabri and enrolling the patient in the TOUCH program physicians acknowledge, in writing, that they understand the Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 17 of 41 PageID: 2189 - 16 - PML risk and must also obtain written acknowledgement from the patient that the patient understands the PML risk. (See Ex. 31 to Marino Cert. - Nelson TOUCH Enrollment Form; Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000012; Ex. 78 to Marino Cert. - June 5, 2006 Re-approval Letter.) 54. Before each Tysabri infusion, a specially trained infusion nurse is required to confirm that the patient has read the Medication Guide, including warnings concerning the PML risk associated with Tysabri. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_0000018-19, 29-34; Ex. 16 to Marino Cert. - Jones Report at p. 46-47; see, e.g. Ex. 32 to Marino Cert. - Nelson TOUCH Form at BIOGEN_NELSON_0000053.) 55. At every monthly Tysabri infusion, the infusion nurse must ask the patient a series of questions concerning their patient’s understanding of the PML risk and ask about new symptoms that suggest a change in neurological condition that could potentially be an early sign of PML. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_000032-33; see, e.g. Ex. 32 to Marino Cert. - Nelson TOUCH Form at BIOGEN-NELSON0000053-54.) 56. If any such changes are reported, the infusion cannot be given without further evaluation and approval of the prescribing neurologist. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label; see, e.g. Ex. 32 to Marino Cert. - Nelson TOUCH Form at BIOGEN- NELSON0000053-54.) 57. The June 5, 2006 FDA re-approval letter to Biogen stated that “Marketing the product [Tysabri] with FPL [final printed labeling] that is not identical to the approved labeling text may render the product misbranded and an unapproved new drug.” (Ex. 78 to Marino Cert. - June 5, 2006 Re-approval Letter.) V. MR. NELSON’S MULTIPLE SCLEROSIS TREATMENT Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 18 of 41 PageID: 2190 - 17 - 58. In 2003, Mr. Nelson began taking a medication called Avonex to treat his multiple sclerosis. (Ex. 45 to Marino Cert. - 9/10/2009 Citak Office Note; Ex. 33 to Marino Cert. - 4/10/2003 University of Iowa Hospitals and Clinics (“U. of Iowa Hospitals”) Note.) 59. Between 2003 and 2006, Mr. Nelson had 2-3 MS relapses. (Ex. 37 to Marino Cert. - 10/13/2006 Yale Neurology Clinic Note.) 60. While taking Avonex, Mr. Nelson experienced side-effects including flu-like symptoms, shaking, chills, post-interferon headache, and malaise. (Ex. 34 to Marino Cert. - 11/3/2004 U. of Iowa Hospitals Progress Note; Ex. 35 to Marino Cert. - 7/20/2005 U. of Iowa Hospitals Note; Ex. 39 to Marino Cert. - 8/27/2007 Yale-New Haven Hospital Record.) 61. In 2005 and 2006, Mr. Nelson’s MS symptoms worsened. In July 2005, Mr. Nelson was feeling weaker and more fatigued. He had increased numbness on the left side of his body, and sometimes found word-finding difficult. He also was having night sweats and lip numbness with nosebleeds and easy bruising. (Ex. 35 to Marino Cert. - 7/20/2005 U. of Iowa Hospitals Note.) 62. In 2006, Mr. Nelson experienced “an episode of numbness of his arms and legs,” and experienced shooting pain down his back and into his arms and legs when he would turn his head. An MRI showed development of new MS lesions. (Ex. 45 to Marino Cert. - 9/10/2009 Citak Office Note.) 63. Mr. Nelson also had extreme fatigue, dizziness and numbness, as well as cognitive clouding and increased spasticity. (Ex. 37 to Marino Cert. - 10/13/2006 Yale Neurology Clinic Note; Ex. 38 to Marino Cert. - 10/24/2006 Yale Neurology Clinic Note.) 64. In 2007 Mr. Nelson experienced increased numbness in his body associated with dizziness and near syncope. (Ex. 45 to Marino Cert. - 9/10/2009 Citak Office Note.) Numbness Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 19 of 41 PageID: 2191 - 18 - was present in his right hand, left upper arm, and both of his feet. He also experienced stiffness in his back and cramping in his calf muscles, the right side more than the left. This was the first time that these problems were seen in his right side (it had always been the left in the past). (Ex. 40 to Marino Cert. - 10/16/2007 Yale Neurology Clinic Note.) In addition, Mr. Nelson had two sensory relapses during 2007. (Ex. 42 to Marino Cert. - 3/4/2008 Yale Neurology Clinic Note.) 65. In December 2007, Mr. Nelson reported that he felt worse than a year ago, and was experiencing fatigue, weakness in both arms, and burning and banding around his waist and legs. (Ex. 41 to Marino Cert. - 12/4/2007 Yale Neurology Clinic Note.) Avonex was not controlling Mr. Nelson’s symptoms. (Ex. 9 to Marino Cert. - Nelson Dep. Tr. at 60:25 – 61:4.) At this point, Dr. Preiningerova discussed with Mr. Nelson the need for more aggressive therapy, specifically Tysabri. (Ex. 41 to Marino Cert. - 12/4/2007 Yale Neurology Clinic Note; Ex. 9 to Marino Cert. - Nelson Dep. Tr. at 61:10-18.) 66. Dr. Preiningerova discussed the risk of PML with Mr. Nelson, and Mr. Nelson spoke with his wife about the possibility of using Tysabri. They were mainly concerned about the risk of developing PML. (Ex. 9 to Marino Cert. - Nelson Dep. Tr. at 61:19-64:20.) 67. During the time that Dr. Preiningerova treated Mr. Nelson, until July 2008, there were no new PML cases. (Ex. 32 to Marino Cert. - Nelson TOUCH Form at BIOGEN- NELSON0000063.) 68. Mr. Nelson’s MS continued to worsen in early 2008, with the presence of new MS lesions and clinical symptoms. (Ex. 42 to Marino Cert. - 3/4/2008 Yale Neurology Clinic Note.) He experienced pain in his chest, stiffness in his legs, banding around his waist when exercising, and Lhermitte’s sign. Mr. Nelson was assessed to have relapsing-remitting multiple sclerosis (“RRMS”) (Ex. 43 to Marino Cert. - 4/10/2008 Yale Neurology Clinic Note.) Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 20 of 41 PageID: 2192 - 19 - 69. Dr. Preiningerova discussed the side effects and risks of Tysabri with Mr. Nelson and prescribed Tysabri to him on April 10, 2008. (Ex. 43 to Marino Cert. - 4/10/2008 Yale Neurology Clinic Note.) 70. Mr. Nelson commenced Tysabri infusions at Yale Apheresis Transfusion Services in Connecticut on May 23, 2008. (Ex. 32 to Marino Cert. - Nelson TOUCH Form at BIOGEN- NELSON0000053.) 71. In July 2008, Mr. Nelson began receiving infusions at Creighton Oncology- Hematology in Nebraska. (Ex. 32 to Marino Cert. - Nelson TOUCH Forms at BIOGEN- NELSON0000063-64.) He continued receiving infusions in Nebraska at Specialty Infusion Center in February 2009. (Ex. 32 to Marino Cert. - Nelson TOUCH Forms at BIOGEN- NELSON0000039-40.) 72. In February 2009, Mr. Nelson started seeing Dr. Rana Zabad in Nebraska for his MS treatment. (Ex. 11 to Marino Cert. - Zabad Dep. Tr. at 92:20-93:17.) Dr. Zabad discussed the risks of Tysabri with Mr. Nelson. Mr. Nelson verbalized his understanding and said that he wanted to continue with the medication. (Ex. 11 to Marino Cert. - Zabad Dep. Tr. at 103:19- 104:5; Ex. 44 to Marino Cert. - 2/3/2009 The Nebraska Medical Center Neurology Clinic Progress Note.) Dr. Zabad’s practice at this time was to warn of PML. (Ex. 11 to Marino Cert. - Zabad Dep. Tr. at 104:15-17.) 73. In February 2009, Mr. Nelson was doing well with Tysabri, with no acute exacerbations of his MS. (Ex. 44 to Marino Cert. - 2/3/2009 The Nebraska Medical Center Neurology Clinic Office Note.) 74. Dr. Zabad had Mr. Nelson’s blood tested for JCV DNA on February 20, 2009, May 19, 2009, and August 7, 2009. Each time, Mr. Nelson’s blood tested negative for the JC Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 21 of 41 PageID: 2193 - 20 - Virus. (Ex. 11 to Marino Cert. - Zabad Dep. Tr. at 124:10-125:2, 136:24-137:4; Ex. 36 to Marino Cert. - The Nebraska Medical Center Lab Report at p. 3.) 75. Mr. Nelson subsequently moved to New Jersey and began receiving Tysabri infusions at Valley Hospital under the care of Dr. Kenneth Citak in September 2009. (Ex. 32 to Marino Cert. - Nelson TOUCH Forms at BIOGEN-NELSON0000022, 73-74; Ex. 45 to Marino Cert. - 9/10/2009 Citak Office Note.) 76. A September 2009 doctor’s note indicates that Mr. Nelson continued to do well on Tysabri and tolerate it well. Dr. Citak discussed the potential side effects of Tysabri with Mr. Nelson at this time. (Ex. 45 to Marino Cert. - 9/10/2009 Citak Office Note.) 77. In July 2010, Mr. Nelson experienced his first MS flare-up since before he started on Tysabri. (Ex. 47 to Marino Cert. - 7/20/2010 Citak Office Note.) 78. Mr. Nelson received his final Tysabri infusion on September 17, 2010. (Ex. 32 to Marino Cert. - Nelson TOUCH Form at BIOGEN-NELSON0000071-72.) 79. In November 2010, Mr. Nelson’s physician ordered a spinal tap to test for JCV in his cerebrospinal fluid (“CSF”), which is the accepted method for diagnosing PML. (Ex. 10 to Marino Cert. - Citak Dep. Tr. at 29:15-30:16.) The test came back negative. (Ex. 10 to Marino Cert. - Citak Dep. Tr. at 29:15-30:16.) In December 2010, Mr. Nelson underwent a brain biopsy which found evidence of PML. (Ex. 49 to Marino Cert. - 12/16/2010 Brain Biopsy Report.) 80. Mr. Nelson was diagnosed with PML in December 2010. (Ex. 1 to Marino Cert. - Complaint at ¶ 65.) VI. MR. NELSON’S TYSABRI TREATMENT AND PML DIAGNOSIS 81. On April 10, 2008, Mr. Nelson signed the TOUCH enrollment form acknowledging his understanding of the PML risk. (Ex. 31 to Marino Cert. - Nelson TOUCH Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 22 of 41 PageID: 2194 - 21 - Enrollment Form.) 82. Dr. Zabad knew about the PML risk when she prescribed Tysabri and discussed the risk with Mr. Nelson. (Ex. 11 to Marino Cert. - Zabad Dep. Tr. at 51:24-52:14, 103:15- 104:17.) 83. Dr. Zabad made a reasonable choice to prescribe Tysabri to Mr. Nelson based upon what was known at the time, including the PML risk. (Ex. 11 to Marino Cert. - Zabad Dep. Tr. at 101:24-102:10, 129:10-129:13, 133:1-6.) 84. Dr. Zabad believed that the Tysabri label adequately warned of the PML risk to permit her to safely prescribe the drug. (Ex. 11 to Marino Cert. - Zabad Dep. Tr. at 131:21- 132:5.) 85. Dr. Zabad was unaware of any prior immunosuppressant use by Mr. Nelson. (Ex. 11 to Marino Cert. - Zabad Dep. Tr. at 107:22-108:11.) 86. Dr. Zabad analyzed whether Tysabri was a reasonable choice for Mr. Nelson and determined that it was. (Ex. 11 to Marino Cert. - Zabad Dep. Tr. at 129:10-13.) 87. Dr. Zabad suspected that there was a duration risk with Tysabri. (Ex. 11 to Marino Cert. - Zabad Dep. Tr. at 91:6-22.) 88. Dr. Zabad knew that use of another immunosuppressive medication could elevate the PML risk. (Ex. 11 to Marino Cert. - Zabad Dep. Tr. at 107:22-109:7.) 89. Dr. Zabad testified that at the time she was treating Mr. Nelson, the Tysabri label adequately warned physicians of the risk of PML. (Ex. 11 to Marino Cert. - Zabad Dep. Tr. at 131:21-132:2.) 90. Dr. Citak was an enrolled TOUCH prescriber who was aware of the PML risk associated with Tysabri at the time he prescribed Tysabri to Mr. Nelson, and understood the Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 23 of 41 PageID: 2195 - 22 - significance of black box warnings. (Ex. 10 to Marino Cert. - Citak Dep. Tr. at 65:5-12, 68:8-11, 96:22-97:12.) 91. Dr. Citak testified that the purpose of the TOUCH program was to make sure that patients and prescribers were aware of the PML risk. (Ex. 10 to Marino Cert. - Citak Dep. Tr. at 68:5-11.) 92. Dr. Citak made a reasonable choice to prescribe Tysabri to Mr. Nelson based upon what was known at the time, including the PML risk. (Ex. 10 to Marino Cert. - Citak Dep. Tr. at 134:13-135:6.) 93. Dr. Citak knew about the PML risk when he prescribed Tysabri and discussed the risk with Mr. Nelson. (Ex. 10 to Marino Cert. - Citak Dep. Tr. at 77:3-79:9, 84:20-85:20, 99:22- 100:1, 117:21-118:2.) 94. Dr. Citak did not recall reviewing the Tysabri package insert. He testified that he is familiar with any medication he prescribes, including Tysabri. (Ex. 10 to Marino Cert. - Citak Dep. Tr. at 93:22-94:8; 140:7-14.) 95. Dr. Citak’s general practice was to obtain information about drugs through medical literature, conferences, and discussions with colleagues. (Ex. 10 to Marino Cert. - Citak Dep. Tr. at 93:22-96:21.) 96. Dr. Citak had no information that the Tysabri label was incorrect or inaccurate. (Ex. 10 to Marino Cert. - Citak Dep. Tr. at 150:14-24.) 97. It is not Dr. Citak’s standard practice to review the package insert for a drug before he prescribes it. (Ex. 10 to Marino Cert. - Citak Dep. Tr. at 93:22-94:8.) 98. Dr. Citak made the independent medical judgment to prescribe Tysabri to Mr. Nelson. (Ex. 10 to Marino Cert. - Citak Dep. Tr. at at 74:5-11.) Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 24 of 41 PageID: 2196 - 23 - VII. DEFENDANTS’ PHARMACOVIGILANCE IN THE POST-MARKETING PERIOD IDENTIFIED THREE PML RISK FACTORS 99. After Tysabri’s re-approval in June 2006, there were no confirmed cases of PML associated with Tysabri use for the remainder of 2006, 2007, and the first half of 2008. (Ex. 94 to Marino Cert. - Safety Review Committee Meeting Minutes (“Safety Minutes”) August 4, 2008.) 100. At the time Tysabri was returned to the market in June 2006, Defendants and FDA considered that the PML risk might be associated with duration of treatment, with the risk increasing with longer treatment duration, but there was insufficient data to support any conclusion. FDA ordered that the Tysabri label in effect when Dr. Preiningerova first prescribed Tysabri for Mr. Nelson expressly warn that “the relationship between the risk of PML and the duration of treatment is unknown.” (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_000018; Ex. 75 to Marino Cert. - November 18, 2005 Letter from Russell Katz, M.D., FDA to Nadine D. Cohen, Biogen; Ex. 76 to Marino Cert. - April 3, 2006 Email from Katherine Needleman, FDA to Paula Sandler, Biogen; Ex. 77 to Marino Cert. - April 26, 2006 Email from Katherine Needleman, FDA to Paula Sandler, Biogen; Ex. 94 to Marino Cert. - Safety Minutes August 4, 2008.) 101. As of June 2006, the two Tysabri associated PML cases in MS patients occurred after a median of 120 weeks of treatment, while the third case in the Crohn’s disease patient occurred after eight doses (32 weeks). This information was expressly stated in the Tysabri label. (Ex. 3 to Marino Cert. - May 22, 2006 Tysabri Label at BIIB_LABEL_000018.) 102. In July 2008, the first two Tysabri-associated PML cases after the reintroduction of Tysabri were confirmed. (Ex. 94 to Marino Cert. - Safety Minutes August 4, 2008; Ex. 79 to Marino Cert. - August 1, 2008 Agency Telephone Contact Report; August 2008 FDA Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 25 of 41 PageID: 2197 - 24 - Information for Healthcare Professionals – Natalizumab Injection for Intravenous Use, available at:http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvi ders/ucm126592.htm (last visited May 12, 2017).) 103. After evaluating the two Tysabri-associated PML cases in July 2008, Biogen requested that FDA update the label to reflect the treatment duration in those cases. In August 2008, FDA approved a Tysabri label stating that Tysabri associated PML can occur in cases of Tysabri monotherapy and further updated the label to state: “There is limited experience beyond two years of treatment. The relationship between the risk of PML and the duration of treatment is unknown, but most cases of PML were in patients who received more than one year of treatment.” (Ex. 5 to Marino Cert. - August 2008 Tysabri Label; Ex. 59 to Marino Cert. - August 1, 2008 FDA Teleconference Meeting Minutes.) 104. By the end of 2008, two additional cases of Tysabri-associated PML were confirmed following the two Tysabri-associated PML cases reported in July 2008 (total of four confirmed Tysabri-associated PML cases in 2008). (Ex. 95 to Marino Cert. - Safety Minutes April 24, 2009; Ex. 72 to Marino Cert. - PML Confirmation Date Chart through November 17.) 105. As of July 24, 2009, there were 11 confirmed cases of Tysabri-associated PML following Tysabri’s reapproval. (Ex. 80 to Marino Cert. - August 5, 2009 Letter from Nadine D. Cohen, Biogen to Russell Katz, M.D., FDA; Ex. 72 to Marino Cert. - PML Confirmation Date Chart through November 17, 2009; Ex. 71 to Marino Cert. - June 2009 Tysabri Update.) 106. Mr. Nelson’s final Tysabri infusion was on September 17, 2010. (Ex. 32 to Marino Cert. - Nelson TOUCH Form at BIOGEN-NELSON-0000071.) 107. In November 2009, while Mr. Nelson was prescribed Tysabri, FDA approved an update to the Tysabri label to read: “In patients treated with Tysabri, the risk of PML increase Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 26 of 41 PageID: 2198 - 25 - with longer treatment duration, and for patients treated for 24 to 36 months is generally similar to the rates seen in clinical trials. There is limited experience beyond 3 years of treatment.” (Ex. 53 to Marino Cert. - September 17, 2009 Press Release; Ex. 96 to Marino Cert. - Safety Minutes September 21, 2009; Ex. 82 to Marino Cert. - September 27, 2009 Email from Tammy Phinney, Biogen to James Reese, FDA; Ex. 81 to Marino Cert. - September 21, 2009 Email from Tammy Phinney, Biogen to James Reese, FDA; Ex. 6 to Marino Cert. - November 2009 Tysabri label at p. 4; Ex. 83 to Marino Cert. - October 16, 2009 Email from Tammy Phinney, Biogen to James Reese, FDA; Ex. 84 to Marino Cert. - November 6, 2009 Letter from Nadine Cohen, Biogen to Russell Katz, M.D., FDA.) 108. In July 2010, while Mr. Nelson was prescribed Tysabri, FDA approved an update to the Tysabri label stating: “The risk of PML is also increased in patients who have been treated with an immunosuppressant prior to receiving Tysabri. This increased risk appears to be independent of Tysabri treatment duration.” (Ex. 7 to Marino Cert. - July 2010 Tysabri Label at P. 4; Ex. 97 to Marino Cert. - Safety Minutes May 14, 2010; Ex. 85 to Marino Cert. - July 12, 2010 Letter from Nadine Cohen, Biogen to Russell Katz, M.D., FDA.) 109. Dr. Citak continued prescribing Tysabri to Mr. Nelson after the warning regarding duration of use was added to the Tysabri label in November 2009. (Ex. 32 to Marino Cert. - Nelson TOUCH Forms; Ex. 6 to Marino Cert. - November 2009 Tysabri Label.) 110. Dr. Citak continued prescribing Tysabri to Mr. Nelson after the warning regarding prior immunosuppressant use was added to the Tysabri label in July 2010. (Ex. 32 to Marino Cert. - Nelson TOUCH Forms; Ex. 7 to Marino Cert. - July 2010 Tysabri Label.) Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 27 of 41 PageID: 2199 - 26 - VIII. MATERIAL FACTS REGARDING THE JCV ANTIBODY ASSAY2/ 111. From 2005 through 2009 there was no published literature correlating the risk of PML with the presence of JCV antibodies circulating in the bloodstream. (Ex. 99 to Marino Cert. - Berger Report at p. 3; Ex. 17 to Marino Cert. - Viscidi Report at pp. 6-7; Ex. 12 to Marino Cert. - Major Dep. Tr. at 411:16-415:18, 418:20-420:8; Ex. 23 to Marino Cert. - Gorelik, L. et al. (2010), Anti-JC Virus Antibodies: Implications for PML Risk Stratification. Ann Neurol., 68: 295–303.) 112. After Tysabri was removed from the market and throughout the time Mr. Nelson was prescribed Tysabri, Defendants devoted research efforts to finding JC virus DNA in the blood and periphery through Polymerase Chain Reaction (PCR) assay testing. PCR testing was thought to be the most likely risk stratification tool due to the fact that in order to develop PML a person must be infected with the JC Virus, and because the virus must move through the body to get to the CNS and mutate into a form that can replicate in CNS tissue. (Ex. 28 to Marino Cert. - Rudick RA, et al. Assessment of JC virus DNA in blood and urine from natalizumab-treated patients. Ann. Neurol. 2010; 68(3):304-310; Ex. 68 to Marino Cert. - Key Take-aways from March 4 PML Expert Panel Meeting; Ex. 99 to Marino Cert. - Berger Report at p. 3; Ex. 12 to Marino Cert. - Major Dep. Tr. at 444:21-445:24; Ex. 17 to Marino Cert. - Viscidi Report at pp. 6- 8.) 113. In 2010, PCR testing in Tysabri patients was found to be “unlikely to be useful” as a PML risk stratification tool in data published in the Annals of Neurology. (Ex. 28 to Marino 2/ Defendants’ position is that facts concerning Biogen’s development of a JCV antibody assay, which was approved in January 2012 (more than a year after Mr. Nelson’s PML diagnosis) is inadmissible in support of Plaintiff’s claims on the grounds that it involves a subsequent remedial measure. It is relevant to aspects of Defendants’ preemption defense and therefore is set forth here. Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 28 of 41 PageID: 2200 - 27 - Cert. - Rudick RA, et al. Assessment of JC virus DNA in blood and urine from natalizumab- treated patients. Ann. Neurol. 2010; 68(3):304-310.) 114. It is common scientific knowledge that antibodies can be evidence of prior exposure to any pathogen, including the JC virus. (Ex. 12 to Marino Cert. - Major Dep. Tr. at 493:1-12.) 115. The mere presence of antibodies does not mean that a person is currently infected with the pathogen, only that at some point in the past the person’s immune system was activated by the presence of the foreign body and produced antibodies. (Ex. 12 to Marino Cert. - Major Dep. Tr. at 400:17-403:21.) 116. A person could develop PML as a result of a primary infection (i.e., first exposure to JCV) at a time when the immune system was being modulated by Tysabri treatment. (Ex. 12 to Marino Cert. - Major Dep. Tr. at 581:22-582:17.) 117. At the time of the first Tysabri-associated PML cases, it was possible that the presence of antibodies would be found to be protective and thus an indicator of decreased PML risk. (Ex. 12 to Marino Cert. - Major Dep. Tr. at 584:24-586:11.) 118. When Tysabri was reapproved in June 2006 there were no statistically significant data (e.g. the additional PML cases that occurred in 2008 and beyond or pre-PML serum samples for patients who later developed PML) from which to determine whether the presence of an antibody would assist in assessing whether someone is at a higher or lower risk of getting PML. (Ex. 12 to Marino Cert. - Major Dep. Tr. at 411:16-416:5, 418:20-420:8, 555:11-561:12.) 119. Although a positive finding on a JCV antibody assay would indicate a necessary prerequisite to JCV infection, without data, a negative finding could not be used as evidence of Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 29 of 41 PageID: 2201 - 28 - decreased PML risk. (Ex. 99 to Marino Cert. - Berger Report at p. 2; Ex. 12 to Marino Cert. - Major Dep. Tr. at 412:9-416:5, 555:25-557:2.) 120. Patients can also change from anti-JCV antibody negative to positive and remain positive in subsequent testing, which is called “seroconversion.” The May 2015 Tysabri label states that the reported rate of seroconversion in patients with MS is 3 to 8 percent annually. (Ex. 8 to Marino Cert. - May 12, 2015 Tysabri label at p. 5.). 121. Biogen continued to conduct research into the potential significance of JCV antibody status in risk stratification, eventually developing an analytically and clinically validated JCV antibody assay and supporting data that lead to FDA clearance of the assay and related Tysabri labeling changes in January 2012. (Ex. 58 to Marino Dec. - October 2006 Material Transfer Agreement; Ex. 61 to Marino Cert. - December 12, 2009 Advisory Board Meeting Minutes; Ex. 70 to Marino Cert. - December 9, 2009 US Regulatory and Safety Expert Panel on PML Risk Stratification; Ex. 62 to Marino Cert. - September 8, 2010, FDA Memorandum of Meeting Minutes; Ex. 63 to Marino Cert. - November 18, 2010 FDA Record of Meeting; Ex. 48 to Marino Cert. - January 2012 Tysabri label.) 122. Biogen continued to search for pre-PML blood samples. In October 2009, Biogen had eight pre-PML blood samples from Tysabri patients who later developed PML available for testing and research, including testing for JCV antibodies. (Ex. 74 to Marino Cert. - November 24, 2009 email chain regarding PML patient samples.) 123. In late 2009, Biogen scientists developed an analytically validated assay that could reliably detect anti-JCV antibodies in the blood. Using the analytically validated assay, Biogen scientists determined that 53.6% of Tysabri-treated MS patients tested positive for JCV antibodies. The assay had not, however, been clinically validated. (Ex. 17 to Marino Cert. - Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 30 of 41 PageID: 2202 - 29 - Viscidi Report at p. 15; Ex. 61 to Marino Cert. - December 12, 2009 Advisory Board Meeting Minutes; Ex. 23 to Marino Cert. - Gorelik, L., et al. (2010), Anti-JC Virus Antibodies: Implications for PML Risk Stratification. Ann Neurol., 68: 295–303.) 124. “Analytically validated” means a JCV antibody assay that has been shown to reliably detect JCV antibodies in order to show prior exposure to the JC virus with an established false positive and negative cutoff. (Ex. 16 to Marino Cert. - Jones Report at p. 22; Ex. 14 to Marino Cert. - August 6, 2014 Guidance for Industry and Food and Drug Administration Staff on In Vitro Companion Diagnostic Devices (by US Department of Health and Human Services) at p. 6.) 125. “Clinically validated” means a JCV antibody assay that has been shown through clinical trial data to be useful to physicians in the clinical setting by providing information regarding the association of JCV antibodies to an individual Tysabri patient’s PML risk. Clinical validation is an FDA requirement for any labeling claim or the marketing of any drug or device for use in the diagnosis or treatment of a disease. (Ex. 16 to Marino Cert. - Jones Report at p. 22; Ex. 14 to Marino Cert. - August 6, 2014 Guidance for Industry and Food and Drug Administration Staff on In Vitro Companion Diagnostic Devices (by US Department of Health and Human Services) at p. 6; Ex. 17 to Marino Cert. - Viscidi Report at pp. 4-5.) 126. When Tysabri was reapproved in June 2006, without the additional PML cases in 2008 and later, and pre-PML serum samples for those patients who got PML, there was no statistically significant data from which to determine whether the presence of JCV antibodies would assist in assessing whether someone was at a higher or lower risk of getting PML. (Ex. 99 to Marino Cert. - Berger Report at p. 4; Ex. 12 to Marino Cert. - Major Dep. Tr. at 411:16- 415:18, 412:9-416:5, 418:20-420:8, 555:11-561:12.) Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 31 of 41 PageID: 2203 - 30 - 127. In late 2009, Biogen Advisory Boards of MS experts and regulatory experts to discuss the data Biogen scientists had developed regarding JCV antibodies using the assay that Biogen had developed. (Ex. 61 to Marino Cert. - December 12, 2009 Advisory Board Meeting Minutes; Ex. 70 to Marino Cert. - December 9, 2009 US Regulatory and Safety Expert Panel on PML Risk Stratification; Ex. 17 to Marino Cert. - Viscidi Report at p. 10.) 128. Most, but not all, of the medical experts at the December 12, 2009 Advisory Board agreed (based on the then-available data) that the idea of using JCV antibody testing in risk stratification could have merit and that Biogen’s research in the area should be pursued. (Ex. 61 to Marino Cert. - December 12, 2009 Advisory Board Meeting Minutes.) 129. At an Advisory Board meeting with US regulatory experts on December 9, 2009, the observation that 11 of 11 patients with pre-PML samples had positive JCV antibodies (using an assay with a seroprevalence rate of 54% in the MS population) was discussed and the general consensus from the regulatory experts was the “data on the assay was too preliminary to be of predictive value” regarding PML at that time. (Ex. 60 to Marino Cert. - December 9, 2009 Advisory Board Meeting Minutes.) 130. On September 8, 2010 and November 18, 2010 representatives of Biogen and Elan met with FDA to discuss Biogen’s anti-JCV antibody assay and related proposed labeling changes based on the data that was available as of that time. True, complete, and accurate copies of FDA’s official meeting minutes are attached to the affidavit of Michael Poirier, Vice President of Asset Management at Biogen. Mr. Poirier attended the meetings with FDA and attests that the official meeting minutes accurately reflect the substance of those meetings. (Ex. 15 to Marino Cert. - Affidavit of Michael Poirier with Exhibits A and B.) Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 32 of 41 PageID: 2204 - 31 - 131. On September 8, 2010, Defendants met with FDA’s Center for Drug Evaluation and Research (“CDER”) to discuss a potential labeling change based on Biogen’s ongoing research regarding JCV antibodies. (Ex. 62 to Marino Cert. - September 8, 2010, FDA Memorandum of Meeting Minutes.) 132. As detailed in FDA’s official meeting minutes on September 8, 2010, due to the insufficiency of available data, FDA rejected Biogen’s proposal to add information to the Tysabri label regarding the significance of JCV antibody status: Sponsor Question 5: Does the Agency agree that the proposed labeling concepts reflect the information that should be provided in the prescribing information for TYSABRI? The proposed labeling concepts are as follows:  Individual anti-JCV antibody status is one consideration in determining the benefit/risk of TYSABRI  Screening for serum anti-JCV antibody should be performed prior to initiating therapy and annually thereafter  Patients who are anti-JCV negative have a lower risk of developing PML than those who are anti-JCV antibody positive  There is an increased risk for PML in anti-JCV antibody positive patients FDA Pre-Meeting Comments: As discussed in the answers above, the Division does not believe that there is currently sufficient information to support the clinical utility of the anti-JCV antibody assay in determining the risk for PML and the benefit/risk of TYSABRI. The Division does, however, agree that the test may be promising and that it should [be] studied carefully to address the concerns identified in our responses. (Ex. 62 to Marino Cert. - September 8, 2010, FDA Memorandum of Meeting Minutes (emphasis added).) 133. FDA’s official meeting minutes from the meeting with Biogen on September 8, 2010, reflect FDA’s concerns regarding the data presented by Biogen, stating among other concerns:  “It is too early in the analysis of this methodology to determine the value of this marker as a PML risk stratification tool”; Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 33 of 41 PageID: 2205 - 32 -  “The results are based on only a small population (only 17 patients had pre-PML antibody status tested)”;  “[W]e do not believe that there is sufficient supporting information at this time to describe the clinical utility of the assay in the approved prescribing information for TYSABRI”;  “It appears that the results you describe are based on testing that was done after patients had already been exposed to Tysabri. It would be more useful, in determining the value of the test, if there were results of serial anti-JCV antibody tests for patients beginning before exposure to Tysabri and then at fixed times following administration of Tysabri (e.g. to identify whether rising antibody titers are predictive of PML)”;  “It is not clear how these results would guide therapy in antibody positive patients”;  “Based on [changes in assay results over time] we are concerned about the stability of the determination, and the utility in using it to predict development of PML”;  “Based on the information you have presented, antibody-negative patients would have a lower risk of developing PML. It is not clear how this information would help guide therapy, particularly given the uncertainty related to the stability of the result in a given individual over time.” (Ex. 62 to Marino Cert. - September 8, 2010, FDA Memorandum of Meeting Minutes.) 134. On November 18, 2010, Defendants again met with FDA regulators, this time at FDA’s Center for Devices and Radiological Health (“CDRH”), to discuss a Biogen proposal to make Biogen’s JCV antibody assay available to Tysabri prescribers as a “laboratory developed test” (“LDT”) kit prior to FDA clearance of the Biogen assay and related labeling changes. (Ex. 63 to Marino Cert. - FDA Record of Meeting November 18, 2010.) 135. On November 18, 2010, FDA again rejected Biogen’s proposal concerning the JCV antibody assay and reiterated in the official meeting minutes FDA’s conclusion that “[t]he usefulness of this test in treatment with Tysabri has not been established.” (Ex. 63 to Marino Cert. - FDA Record of Meeting November 18, 2010.) Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 34 of 41 PageID: 2206 - 33 - 136. As reflected in FDA’s official meeting minutes from the meeting with Biogen on November 18, 2010, FDA stated that Biogen’s JCV antibody assay could not be made available for use with Tysabri until the antibody assay was cleared by FDA for use in the clinical setting as a medical device and a labeling change for Tysabri was approved after the submission of clinical data. FDA’s official meeting minutes document FDA’s concerns regarding the sufficiency of Biogen’s JCV antibody assay data, stating among other comments:  “If the drug labeling specifies this device as critical in order to determine therapy, the sponsor/test must comply with FDA regulations for in vitro diagnostic devices”;  “The information provided does not allow us to determine the clinical utility for the intended use claims”;  “Regarding the analytical accuracy studies performed, you have evaluated the analytical accuracy versus urine shed viral DNA. This is not a valid comparator as the antibodies demonstrate prior exposure to the virus and are not comparable to urine shed viral DNA which may or may not occur in association with a JCV infection and latency in the kidneys or elsewhere in the urinary tract”;  “Your proposal to assess the agreement between your commercial kit and your LDT test (which is essentially the same device) is not acceptable as a means to evaluate your device performance. As stated above, we recommend that you assess the clinical performance of your device in the context of the drug trial”;  “The risk and hence the classification of the device cannot be determined until its use is established via the drug label”;  “CDRH expressed concerns about the stability of the antibody response based on the data submitted to the agency in the briefing document”;  “This specific assay does not have any intended use other than to be used with the drug. Therefore, an LDT could not be cleared/approved before the assay is mentioned in the drug label”;  “It was noted that the anti-JCV antibody assay has limited positive predictive value as an independent risk factor, but it may have potential benefits within an algorithm which considers other risk factors. CDER will evaluate these issues during review of the sBLA submission, which will include additional analyses related to anti-JCV antibody testing results and their clinical utility”; Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 35 of 41 PageID: 2207 - 34 -  “The final decision regarding the utility and drug label modification will be determined by CDER subsequent to the evaluation of the sBLA”;  “The Agency confirmed that an LDT clearance for the proposed indications could only take place after the clinical division had approved the label change that described the clinical utility of the assay.” (Ex. 63 to Marino Cert. - FDA Record of Meeting November 18, 2010.) 137. In light of FDA’s rejection of a labeling change in September 2010, and rejection of making Biogen’s assay available to physicians based on the insufficiency of the available scientific evidence concerning its clinical utility in November 2010, over the course of the next year Biogen continued to sponsor the STRATIFY clinical trials (which began in March 2010), and worked with FDA to demonstrate the usefulness of the assay in the clinical setting. (Ex. 86 to Marino Cert. - December 21, 2010 Letter from Nadine D. Cohen, Biogen to Russell Katz, M.D., FDA; Ex. 87 to Marino Cert. - April 15, 2011 Letter from Nadine D. Cohen, Biogen to Russell Katz, M.D., FDA; Ex. 88 to Marino Cert. - April 29, 2011 Letter from Nadine D. Cohen, Biogen to Russell Katz, M.D., FDA; Ex. 91 to Marino Cert. - November 5, 2011 Letter from Nadine D. Cohen, Biogen to Russell Katz, M.D., FDA; Ex. 89 to Marino Cert. - May 13, 2011 Letter from Nadine D. Cohen, Biogen to Russell Katz, M.D., FDA; Ex. 90 to Marino Cert. - May 27, 2011 Letter from Nadine D. Cohen, Biogen to Russell Katz, M.D., FDA; Ex. 93 to Marino Cert. - December 9, 2011 Letter from Nadine D. Cohen, Biogen to Russell Katz, M.D., FDA.) 138. Biogen sponsored two clinical trials related to JCV antibodies and Tysabri use, collecting blood samples from Tysabri patients for research purposes: STRATIFY-1 and STRATIFY-2. Both clinical trials enrolled their first patients in March 2010. The purpose of STRATIFY-1 was “to define the prevalence of anti-JC virus (JCV) antibodies in multiple sclerosis (MS) patients and to evaluate the analytical false-negative rate of a 2-step anti-JC virus antibody assay.” The purpose of STRATIFY-2 was to “demonstrate that the incidence of Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 36 of 41 PageID: 2208 - 35 - progressive multifocal leukoencephalopathy (PML) in natalizumab-treated participants who do not have detectable antibodies to John Cunningham virus (JCV) (antibody negative) is lower than in participants who have detectable antibodies to JCV (antibody positive).” (Ex. 19 to Marino Cert. - Bozic, C., Anti-John Cunningham Virus Antibody Prevalence in MS Patients: Baseline Results of STRATIFY-1, August 10, 2011; Ex. 20 to Marino Cert. - Bozic, Anti-JCV Antibody Prevalence in Patients with Relapsing MS Receiving or Considering Treatment with Natalizumab: Baseline Results of STRATIFY-2, April 26, 2012.; Ex. 73 to Marino Cert. - ClinicalTrials.gov Description of STRATIFY-2; Ex. 16 to Marino Cert. - Jones Report at pp. 52- 53.) 139. In October 2011, Biogen again requested FDA allow the Tysabri label to be amended to include information concerning the significance of JCV antibodies based on data from ongoing research and clinical trial data. (Ex. 92 to Marino Cert. - October 5, 2011 Letter from Nadine D. Cohen, Biogen to Russell Katz, M.D., FDA.) 140. The October 2011 submission from Biogen to FDA proposing a Tysabri label change regarding the significance of JCV antibodies included data showing 37 of 37 pre-PML blood samples that were positive for JCV antibodies at that time using an assay that determined the background “seropositivity” rate in the MS population was 54%. (Ex. 92 to Marino Cert. - October 5, 2011 Letter from Nadine D. Cohen, Biogen to Russell Katz, M.D., FDA; Ex. 16 to Marino Cert. - Jones Report at pp. 52-53.) 141. On January 20, 2012, FDA announced it had cleared the STRATIFY JCV antibody assay and approved an associated Tysabri labeling change regarding the significance of JCV antibodies. FDA issued a press release announcing that this antibody test was the “first test Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 37 of 41 PageID: 2209 - 36 - for risk of rare brain infection in some people treated with Tysabri.” (Ex. 54 to Marino Cert. - January 20, 2012 FDA News Release; Ex. 48 to Marino Cert. - January 2012 Tysabri Label.) IX. DR. CITAK TESTIFIED TO THE LIMITED UTILITY OF THE ANTI-JCV ANTIBODY ASSAY WHILE HE WAS TREATING MR. NELSON 142. If Biogen had developed a JCV antibody assay earlier, it would have had limited utility to Dr. Citak because he would not have known what do with the result for lack of data. Similarly, a warning regarding JCV antibodies would not have made a difference without a commercially available test for JCV antibodies. (Ex. 10 to Marino Cert. - Citak Dep. Tr. at 147:6-148:5.) 143. Dr. Citak would not have used an anti-JCV antibody assay unless there was published scientific data establishing the significance of the assay’s findings to PML risk. (Ex. 10 to Marino Cert. - Citak Dep. Tr. at 115:18-25, 123:16-124:12, 146:25-147:21.) 144. Dr. Zabad testified that consistent, reproducible data is necessary to understand the significance of an antibody test result. (Ex. 11 to Marino Cert. - Zabad Dep. Tr. at 180:6-10.) X. EXPERT TESTIMONY 145. Plaintiff’s only expert in this case is Eugene Major, Ph.D. 146. Major is not a medical doctor or neurologist. (Ex. 12 to Marino Cert. - Major Dep. Tr. at 142:14-17, 142:20-21, 143:24-144:3, 144:14-25). 147. Major is not qualified to opine on the adequacy of the drug’s labeling or FDA labeling requirements. (Ex. 12 to Marino Cert. - Major Dep. Tr. at 239:12-18). 148. Major’s expert report does not comment on the adequacy of the Tysabri labeling and he does not offer any opinion regarding the adequacy of the label at his deposition. (Ex. 12 to Marino Cert. - Major Dep. Tr. at 466:18-467:5 (“I’m not going to comment on the labeling.”); Ex. 18 to Marino Cert. - Expert Report of Dr. Eugene Major (“Major Report”) at pp. 10-11). Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 38 of 41 PageID: 2210 - 37 - 149. Major is not a regulatory expert. (Ex. 12 to Marino Cert. - Major Dep. Tr. at 147:6-149:15, 183:6-8 (“I am not a regulatory expert.”).) 150. Major is not familiar with the regulatory requirements for prescription drug labels. (Ex. 12 to Marino Cert. - Major Dep. Tr. at 212:11-213:1.) 151. Major did not review the Tysabri regulatory file in preparing his expert report. (Ex. 12 to Marino Cert. - Major Dep. Tr. at 121:4-21.) 152. Major does not offer an opinion in his report on Biogen’s or Elan’s conduct and disavowed at his deposition any intention to do so. (Ex. 18 to Marino Cert. - Major Report at pp. 10, 11; Ex. 12 to Marino Cert. - Major Dep. Tr. at 186:8-21.) 153. Major offers no opinions related to the duration warning or prior immunosuppressant warning. (Ex. 18 to Marino Cert. - Major Report at pp. 10-11.) 154. Major states in his report that Biogen could have developed a “commercially available” JCV antibody assay by 2007 and “[u]nder the circumstances it would have been reasonable for Biogen to communicate to patients through the TOUCH program, whose purpose is to educate physicians and patients on the risk of PML, that JC Virus causes PML and therefore prior exposure as measured by the presence of antibody was a factor in the assessment of the risk.” (Ex. 18 to Marino Cert. - Major Report at pp. 10-11). 155. But Major does not know what was required to commercialize the STRATIFY JCV Antibody Assay, nor does he know what Biogen did to commercialize the assay. (Ex. 18 to Marino Cert. - Major Dep. Tr. at 161:13-162:6, 166:14-168:7, 175:16-176:16, 181:23-183:2.) 156. Major’s report states: “It would therefore have been prudent for Biogen to communicate to physicians, healthcare providers and patients that the JC Virus Antibody test Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 39 of 41 PageID: 2211 - 38 - might be useful in helping to assess a higher risk of PML.” (Ex. 18 to Marino Cert. - Major Report at p. 9). 157. Major made the assumption that [FDA] would have final responsibility for the TOUCH program. (Ex. 12 to Marino Cert. - Major Dep. Tr. at 148:11-150:8.) 158. During the time Mrs. Amos was treated with Tysabri there were no statistically significant data concerning the significance of anti-JCV antibodies in relation to PML risk. This fact is undisputed, and Major admitted this fact. (Ex. 12 to Marino Cert. - Major Dep. Tr. at 411:16-415:18, 418:20-420:8.) XI. COURTS HAVE FOUND UNDISPUTED FACTS ON THE SAME FDA REGULATORY FILE IN RELATED CASES 159. Three similar Tysabri cases have reached the summary judgment phase. These cases are Christison v. Biogen Idec Inc. and Elan Pharmaceuticals, LLC, No. 2:11-cv-01140- DN-DBP, 2016 U.S. Dist. LEXIS 110273 (D. Utah Aug. 5, 2016); Gentile v. Biogen Idec, Inc. and Elan Pharmaceuticals, LLC, No. 1181 CV 03500, 2016 Mass. Super. LEXIS 238 (Mass. Sup. Ct. July 25, 2016); and Amos v. Biogen Idec Inc. & Elan Pharm., No. 6:13-cv-06375 (W.D.N.Y. Apr. 10, 2017) (unpublished) (Ex. 100 to Marino Cert.). 160. Biogen and Elan submitted statements of undisputed fact accompanying their summary judgment briefs in Christison, Gentile, and Amos. The FDA regulatory record in these two cases is identical to the FDA regulatory record in this case. 161. All three courts granted summary judgment to Biogen and Elan on all counts. See Christison, No. 2:11-cv-01140-DN-DBP, 2016 U.S. Dist. LEXIS 110273 (D. Utah Aug. 5, 2016); Gentile, No. 1181 CV 03500, 2016 Mass. Super. LEXIS 238 (Mass. Sup. Ct. July 25, 2016); and Amos, No. 6:13-cv-06375 (W.D.N.Y. Apr. 10, 2017) (unpublished) (Ex. 100 to Marino Cert.) Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 40 of 41 PageID: 2212 - 39 - Respectfully submitted, BIOGEN INC., & ELAN PHARMACEUTICALS, LLC By their attorneys, ____________________________ Kevin H. Marino kmarino@khmarino.com John D. Tortorella jtortorella@khmarino.com MARINO, TORTORELLA & BOYLE, P.C. 437 Southern Boulevard Chatham, NJ 07928 Tel: (973) 824-9300 Fax: (973) 824-8425 - and - Joseph G. Blute (admitted pro hac vice) jblute@mintz.com Yalonda T. Howze (admitted pro hac vice) ythowze@mintz.com MINTZ, LEVIN, COHN, FERRIS, GLOVSKY & POPEO, PC One Financial Center Boston, MA 02111 Tel: (617) 542-6000 Fax: (617) 542-2241 Case 2:12-cv-07317-JMV-MF Document 154-2 Filed 05/15/17 Page 41 of 41 PageID: 2213 Kevin H. Marino John D. Tortorella MARINO, TORTORELLA & BOYLE, P.C. 437 Southern Boulevard Chatham, New Jersey 07928-1488 Telephone: (973) 824-9300 Fax: (973) 824-8425 e-mail: kmarino@khmarino.com OF COUNSEL: Joseph G. Blute (admitted pro hac vice) Yalonda T. Howze (admitted pro hac vice) MINTZ, LEVIN, COHN, FERRIS, GLOVSKY AND POPEO, P.C. One Financial Center Boston, Massachusetts 02111 Tel: (617) 542-6000 Fax: (617) 542-2241 e-mail: jgblute@mintz.com Attorneys for Defendants Biogen Inc. & Elan Pharmaceuticals, LLC UNITED STATES DISTRICT COURT DISTRICT OF NEW JERSEY ANDREW NELSON, Plaintiff, v. BIOGEN INC. AND ELAN PHARMACEUTICALS, LLC, Defendants. Hon. John M. Vazquez, U.S.D.J. No. 2:12-cv-7317-JMV-MF ORDER GRANTING SUMMARY JUDGMENT TO DEFENDANTS THIS MATTER having been opened to the Court upon the motion of Defendants Biogen Inc. and Elan Pharmaceuticals, LLC (collectively, “Defendants”), through their attorneys Marino, Tortorella & Boyle, P.C., for entry of an Order, pursuant to Fed. R. Civ. P. 56, granting summary judgment in favor of Defendants on Plaintiff’s claim with prejudice; and the Court having considered the submissions of the parties and oral argument of counsel; and good cause having been shown; IT IS ON THIS _____ day of _________________, 2017, Case 2:12-cv-07317-JMV-MF Document 154-3 Filed 05/15/17 Page 1 of 2 PageID: 2214 2 ORDERED that Defendants’ motion for summary judgment is GRANTED; and IT IS FURTHER ORDERED that Plaintiff’s Fourth Amended Complaint is DISMISSED WITH PREJUDICE. _____________________________________________ Honorable John Michael Vazquez, U.S.D.J. Case 2:12-cv-07317-JMV-MF Document 154-3 Filed 05/15/17 Page 2 of 2 PageID: 2215