BRACCO DIAGNOSTICS, INC., Plaintiff, v. AMERSHAM HEALTH, INC., et al., Defendants, 627 F. Supp. 2d 384

AMENDED OPINION FREDA L. WOLFSON, District Judge. Glossary of Abbreviations AHI Amersham Health Ine. (U.S.-based Counterclaim Plaintiff) ASD GEH Area Sales Director AWC Adequate and well-controlled study BDI Braceo Diagnostics Inc. [witness] D Designated deposition testimony [witness] Dec Designated declaration CE Continuing Education for doctors, nurses and technicians CIN Contrast Induced Nephropathy or renal damage caused by x-ray contrast medium CM Contrast Medium or Contrast Media CME Continuing Medical Education for doctors CMS Centers for Medicare and Medicaid Services CT Computer Tomography.

A type of x-ray procedure where the CM is given by i.v. administration CT DCAM Novation’s DCAM for CT (i.e., x-ray) contrast media CT+MR DCAM Novation’s DCAM for both CT (i.e., x-ray) and MR contrast media Cx Braeco’s Proposed Post-Trial Conclusion Of Law at paragraph “x” Dx: y Defendant’s Trial Exhibit “x” at page “y” (where y is the last three numbers of a Bates number, if applicable) DCAM Decision Criteria Award Matrix DHRxns Delayed Hypersensitivity Reactions Dual DCAM Novation’s DCAM for a dual source award for both CT (i.e., x-ray) and MR contrast media EC Financial Criteria FDA United States Food and Drug Administration GEH GEH Healthcare, which acquired the three named defendants, who in turn acquired Amersham and Nycomed GPO Group Purchasing Organization HOCM High Osmolar Contrast Medium intra-arterial (form of administration directly into an artery) Intra-venous (form of administration directly into a vein) IOCM GEH’s trademarked term, Isosmolar Contrast Medium ITB Novation’s June 14, 2004 “Invitation To Bid” JACC Journal of the American College of Cardiology KOL Key Opinion Leader LBB “Low Best Bid” or “Low Best Bidder” LOOM Low Osmolar Contest Medium MA Meta-Analysis, a type of clinical study analysis MACE Major Adverse Cardiac Events or Major Adverse Clinical Events, depending on the study design MRDCAM Novation’s DCAM for MR contest media MRI magnetic resonance imaging contrast media NAC N-acetylcysteine NEJM New England Journal of Medicine NFC Non-Financial Criteria NQWMI Non-Q-wave Miocardial Infarction RFA GEH’s responses to Braeeo’s requests for admissions RFP GPO Request For Proposal OTSheet Omnipaque Toss Sheet Px:y Plaintiff’s Trial Exhibit “x” at page “y” (where y is the last thi-ee numbers of a Bates number, if applicable) PCI percutaneous cardiac intervention PO Pretrial Order POA Plan of Attack or Plan of Action PTCA Percutaneous Transluminal Coronary Angioplasty SR Systematic Review (type of clinical study analysis) TCT Transcatheter Cardiovascular Therapeutics (TCT) Scientific Symposium TF Novation’s ICM Task Force URTBrochure Unchallenged Renal Tolerability Brochure xTy Trial Transcript Volume “x” at page “y” WAT Visipaque Value Analyis Tool Contrast Agents Isovue Braceo x-ray contrast agent ProHance Braceo MRI contrast agent MultiHance Braceo MRI contrast agent Visipaque GEH x-ray contrast agent Omnipaque GEH x-ray contrast agent Omniscan GEH MRI contrast agent Optiray Tyeo/Mallinckrodt x-ray contrast agent Hexabrix Tyeo/Mallinckrodt x-ray contrast agent This matter comes before the Court upon a Complaint brought by Plaintiff Braceo Diagnostics Inc. (referred to herein as “Braceo”) against Defendants Amersham Health Inc., Amersham Health AS, and Amersham PLC (collectively referred to herein as “GEH”) for alleged false advertising in violation of the Lanham Act.

In response, GEH filed a Counterclaim against Braceo for alleged false advertising of its own line of products. Braceo and GEH have competing product lines in the contrast medium healthcare industry. The crux of Bracco’s case is that GEH has falsely advertised the superiority of its product, Visipaque, over Bracco’s product, Isovue. The Court conducted a thirty-nine day bench trial with numerous experts and witnesses testifying as to each party’s product lines and the underlying clinical studies upon which GEH and Braceo have based their advertising campaigns.

In light of the evidence presented at trial, the Court concludes that GEH did promote false messages which were sufficient in number to constitute actionable commercial advertisements or promotions under the Lanham Act, however the Court finds that Braceo has failed to establish a causal nexus between GEH’s false advertisements and Bracco’s alleged lost profit damages. In that regard, the Court determines that the greater number of GEH’s advertisements were in fact true and based on reliable scientific studies. The messages that the Court finds false are those that extrapolate beyond the studies’ results.

In connection with Bracco’s claim, the Court finds that an injunction and damages for post and future corrective advertising are appropriate remedies to prevent future violations of the Lanham Act. As to GEH’s counterclaim, GEH dismissed its claim for damages and Braceo has stipulated that it no longer uses the offending advertisements. Thus, although the Court finds that certain of Bracco’s ads were false, nonetheless, an injunction is not appropriate in this case. In addition, the Court imposes an alternative dispute mechanism applicable to both parties for safeguarding against any future false advertisements.

I. Overview A. Parties and Product Lines GEH and Braceo market and sell x-ray contrast media (“CM”) in the United States. CM are classified by osmolality. HOCM (high osmolar CM) have osmolalities of greater than 1500 mOsm/kg. LOCM (low osmolar CM) have osmolalities between 600 and 850 and include Omnipaque (iohexol), Isovue (iopamidol), Hexabrix (ioxaglate), Ultravist (iopromide), Iomeron (iomeprol), and Optiray (ioversol). The osmolality of blood is approximately 290 mOsm/kg. Both GEH and Braceo market LOCM; GEH sells Omnipaque and Braceo sells Isovue.

In addition, GEH also markets a product called Visipaque (iodixanol) which it classifies as isoosmolar or isotonic, (i.e.-its osmolality equals blood). Visipaque is referred to in various medical literature as an IOCM (iso-osmolar CM). Part of GEH’s advertising campaign is that its iso-osmolar CM performs better than LOCM. Visipaque was introduced in 1996, ten years after Omnipaque and Isovue were marketed and is the only “IOCM” available in the U.S. B.

Procedural History On December 16, 2003, Braceo filed a four count Complaint in the District of New Jersey against GEH alleging: (1) dissemination of false and misleading advertisements in violation of

Section 43(

a) of the Lanham Act; and

(2) N.J.S.A. 56:4-1, et seq.; (3) violations of the common law of unfair competition; and (4) negligent misrepresentations. GEH filed an Answer and two counterclaims against Braceo alleging: (1) dissemination into commerce of allegedly false and misleading statements concerning the relative safety of Omnipaque, Visipaque, and Isovue in violation of

Section 43(

a) of the Lanham Act; and

(2) N.J.S.A. 56:4-1, et seq. GEH’s counterclaim was filed against Braceo and its foreign affiliates, Braceo S.p.A. and Braceo Imaging S.p.A. However, pursuant to an Order entered on September 7, 2004, GEH’s counterclaim against Bracco’s foreign affiliates was dismissed for lack of personal jurisdiction. Motions for

Summary Judgment were denied by the Court, after which, a thirty-nine day bench trial was conducted between the period of May 7, 2007 and December 2007, followed by further written submissions. The Court held a hearing on May 15, 2008, wherein the Court resolved evidentiary objections regarding the admission of disputed exhibits. Subsequently, the parties submitted proposed Findings of Fact and Conclusions of Law, which were supplemented by Reply briefs and additional Daubert briefs to exclude expert testimony proffered by both sides. II. Findings of Fact A.

Bracco’s Case in Chief As set forth below, the Court finds that GEH advertises and promotes Visipaque with establishment claims asserting that studies show it is superior in several ways, including renal and cardiovascular safety, pain, heat and discomfort.

The Court further finds that: the spike in Visipaque sales that started in 2003 was primarily due to the publication of the NEPHRIC study; GEH’s advertising of NEPHRIC through true renal ads and promotions also contributed significantly to GEH’s success with Visipaque; only a fraction of GEH’s ads were false; while these false ads were sufficient in number to constitute actionable promotions under the Lanham Act, they were not the cause of GPO contracts being awarded to GEH.

In addition, the Court finds that the limited false ads disseminated by GEH were not willfully false because GEH relied on scientific studies, which have not been disproved, and that GEH had a protocol in place for approving advertisements that attempted to ensure against falsity. 1.

GEH’s Establishment Claims Of Renal Superiority In late 2002 to early 2003, GEH focused its ads and promotions on renal establishment claims based on the NEPHRIC study; GEH claimed that Visipaque had superior renal safety over competitor drugs or LOCM. (See, e.g., P1672 (“[w]e will begin to shift our focus from a Excellent Patient Comfort/Cardiac Safety message to the prime message being Excellent Renal Tolerance”), P106, P849:932, P1269:219, P1147:261, P1265:203, P1266:208; 13 T 72, 16 T 95, 6 T 58-79,102-104, 17 T 69-70). These claims are of two types: the data (from NEPHRIC or other studies) show (

a) Visipaque is superior to a LOCM or all LOCM or (

b) Visipaque is as good as or better than LOCM with pretreatments. GEH uses the term LOCM to obscure the fact that its own drug, Omnipaque, was the comparator in the NEPHRIC study, and to thereby lessen any impact on Omnipaque, specifically, and to generalize the results to all LOCM, including Isovue. (P1534, P1535, P1519, P1523; 13 T 62-63). GEH designed and then planned to disseminate the claims through multiple promotional channels (print media, websites, GEH representatives, medical doctors and CME’s). (8 T 4-15,81-129, 135-37, 17 T 53,64-68; P869 (’03), P849 (’04), P2098 (’05)).

GEH determined that the claims were the most effective way to convert sales based on its experience, (e.g., 7 T 178), and marketing research (P196, P696, P1400, P1700, P1716:739, P1742, P2038; 13 T 27-28).

The GEH representatives were instructed in Plans of Action (“POA”) (e.g., P210L559 (e.g., “less incidence of CIN”)), memoranda (e.g., P102 (“top 3 messages”), PI04, P353, P398:394, P639:552 (“(CIN) in high-risk patients was 11X less likely ... than with LOCM”), P640, P661, P662, P696, P772, P1832:194, P2027, P4249; D790), training (e.g., P651 (e.g., ‘Visipaque is clinically proven to be ... safer for high risk patients”), P1136:370 (“safer”)) and Medical Bulletins (e.g., P402:563 (e.g., “NEPHRIC data clearly demonstrate ... a significantly better renal safety profile than a traditional [LOCM], such as iohexol, in at-risk patients”), P538:888, P798:078) to disseminate the claims. (E.g., P85, P632, P774, P1008, P1012, P1021, P1080, P1082, P1136, P1178, P1373:182, P1561, P1572:893, P1681, P1699, P1721, P2099, P2100, P2101, P3708; 8 T 68-81, 129-135, 148-80, 9 T 5-53, 65-80, 88-102).

The claims were then disseminated nationwide using print media, GEH representatives and continuing medical education (“CME”) presentations.

The print media (e.g., brochures, websites, presentations, articles) with extracted messages that were identified in Bracco’s pretrial brief and discovery responses and addressed at trial include: • Press releases on its website: “[]The NEPHRIC data clearly demonstrate that VisipaqueTM offers a significantly better renal safety profile than traditional low osmolar non-ionic contrast media in at-risk patients---- We believe that the data strongly support Visipaque as the agent of choice for these patient groups.” P2449:379, P69:915, P254:863, P772:340, P1448:898, P4149:p2; 7 T 68-69. • Computer Tomography (CT) brochures: “Nonionic Dimer Provides Lower Osmolality, Reduced ...

CIN” “CIN”: “Nonionic Dimer”: “Nonionic Monomer”: “f”. P410:965, 3649:408, 3649A:408; D2324:117. • Novation presentation: “Isosmolar VISIPAQUE ... Demonstrated to significantly reduce incidence of Contrast-induced Nephropathy (CIN).” P2161:391. GEH rep efforts included the delivery of the claims and print media in face-to-face detailing of administrators, technicians, nurses and doctors, for which records were presented at trial from GEH’s sales call record system, emails and memoranda, e.g.” • Sales Calls Records: “Discussed patient types that would benefit from Visipaque usage over Isovue.

Re-affirmed with Nephric study.” P2312:A637284, P4049:A637284. “Discussed having hospital start using Visipaque for high-risk patients in CT. Detailed Nephric study and core visual aid to support benefits of isosmolar Visipaque vs. Isovue.” P2312:A637355, P4049:A637355. “[CJlinical studies, nephric etc show less risk nephrotox vs ... Isovue for [high risk] pts .... ” P2312:A659673, P4049:A659673. “reviewed why Visi. is the best for kidneys.” P2312:A670058, P4049A670058. “Approached dr. with nephric focus and differentiating vis from loem class with regards to osmoality.

Reminded dr. that patients are 11 times likely to have CIN with the loem class than visi.” P3682:Omni/3727,4049:Omni/3727. • Consorta detailing: “Baluchi [from Consorta] asked about Isovue with respect to Omnipaque/LOCM as positioned in NEPHRIC. We made the point that Omnipaque represents a LOCM (gold standard) and confirmed his key take away that it is iso-osmolar versus low-osmolar that was studied, not necessarily Visipaque vs.

Omnipaque.” P682:286. “I ... discussed the attributes of Isosmolar Visipaque including it’s impact on CIN-a clinical issue just coming to light; it’s elimination of costly drug therapies (fenladopan) to prevent CIN with std LOCM”. P793:514. • HPG detailing: “Ami presented the Nephric data to Lew and he was very interested in the info. He told her that one criticism of this paper was that it was not a head to head with Isovue.

Ami showed him the list of references that prove the incidence of CIN with Isovue is equal to that of Omnipaque so it is reasonable to draw a correlation that the results of Nephric would be the same if Isovue had been used. ” P663:942 (emphasis added).

The Court also finds that GEH-sponsored CME presentations for doctors (e.g., P849:946) delivered IOCM versus LOCM claims: • 2001 CME On CIN: “[R]ecent controlled trials have shown that non-ionic Iso-osmolar contrast agents are superi- or to low-osmolar agents in preventing CIN.” P425L210 (emphasis added). “The use of iodixanol in at-risk patients appears to minimize the risk of CIN even without additional pharmacological prophylaxis.” P425L212. At trial, GEH’s sales rep, Mr.

Joseph Murray, confirmed delivering these claims through the print media (e.g., press releases and articles) and CME-type presentations to customers in order to convert sales to Visipaque. (E.g., 16 T 31-49, 56-58, 81-88, 97-114; 17 T 49-51, 64-132). 2.

The Falsity Of GEH’s Renal Establishment/Superiority Claims The Court finds that certain assertions made by GEH were supported by the studies’ (NEPHRIC and Chalmers) conclusions (e.g. — Visipaque may be renally superior over a LOCM — Omnipaque), while others were not (i.e.- — Visipaque may perform better than LOCM with prophylactics and Visipaque is renally superior over all LOCM). Braceo asserts that GEH’s representations are false and misleading because: (

a) the NEPHRIC study omitted results and has flaws that contradict GEH’s claims (Pl.’s FOF ¶¶ 11-15, 17); (

b) the studies (NEPHRIC and Chalmers) cannot reliably (Pl.’s FOF ¶¶ 11-13) support a conclusion of Visipaque superiority over all LOCM; and (

c) the weight of the clinical evidence is that Visipaque is not superior to all LOCM as a group or to Isovue individually (Pl.’s FOF ¶¶ 11-15, 17). For example, Braceo asserts that results of studies done with intra-arterial (“i.a.”) use are not reliable enough to predict with reasonable certainty intravenous (“i.v.”) results, (see P1733)11; furthermore, Braceo points out that no studies compare Visipaque to a LOCM combined with pretreatments or even head-to-head with multiple LOCM.

The Court finds: (1) while there were flaws in NEPHRIC, those flaws do not vitiate its results; (2) the NEPHRIC and Chalmers studies are not unreliable in their conclusions; and (3) it has not been established by the weight of clinical evidence that Visipaque is superior to all LOCM as a group or to Isovue individually. Although there has never been one adequate and well-controlled (“AWC”) clinical study (let alone two, done the same way with the same drug) showing that Visipaque is superior to any LOCM (even Omnipaque), with or without pretreatments,13 the Lanham Act does not demand such a rigorous finding.

Nonetheless, although not dispositive, the FDA agrees with the Court’s findings in numerous letters sent to GEH, including one as recent as March 21, 2005, where it states that the results of the NEPHRIC study cannot be extrapolated to CM other than Omnipaque in GEH advertising. (P1894.) To lay the foundation for Bracco’s claims, and GEH’s defenses, the parties first presented background clinical evidence at trial.

The following pertains to such evidence: randomization in a clinical trial increases its reliability; a primary endpoint is a clinically relevant endpoint around which a study is designed; studies may also have secondary endpoints, which are of interest but are deemed to be of less importance to the study investigators; a MA is a statistical combination of results from multiple studies; a p-value is a statistical measure that provides a general estimate of the probability that two tested clinical strategies are different; furthermore, the probability that two treatments are different can be roughly estimated as 1 minus the p-value.

After laying a foundation for generalized information regarding the

interpretation of medical studies, the parties presented specific clinical evidence in connection with GEH’s claim that Visipaque is less nephrotoxic than other LOCM. Changes in renal function are commonly measured by serum creatinine (“SCr”). Dr. Peter Aspelin, an M.D., Ph.D., a professor of medicine in Stockholm, and the author of NEPHRIC, testified that CIN is commonly defined as an increase in SCr up to 3 days of 0.5 mg/dL, 25%, or both, and that rises in SCr after 3 days may be due to factors other than administration of CM.

Braceo disputes this definition of CIN; it contends that rises in SCr after three days are significant. The Court need not determine the clinical significance of CIN after three days because while I find that such data is relevant to the weight given to a study’s conclusions, here I find that the use of either definition would not make the underlying study unreliable. Nonetheless, it is undisputed that patients with both renal insufficiency (RI) and diabetes are at a higher risk for developing CIN, than patients with only RI or only diabetes. In addition, Dr. Harold I.

Feldman, an expert in internal medicine and nephrology, proffered by GEH, testified that patients with only diabetes have a lower risk than patients with only RI and that greater contrast volume increases a patient’s risk of CIN, while N-acetylcysteine (NAC) or sodium bicarbonate may reduce CIN. Furthermore, it was established at trial, through expert testimony and exhibits, that there is a scientifically reasonable and widely held belief in the medical community that LOCM are less nephrotoxic than HOCM due to the reduced osmolality of LOCM. This belief is also shared by Braceo. As to LOCM, Dr.

Feldman testified at trial, that as of February 2003, there was little evidence of differences in nephrotoxicity between Omnipaque and Isovue. Bracco’s Dr.

Spinazzi testified, and published to his peers, that as of the date NEPHRIC was published, it was believed that all nonionic LOCM performed similarly even though he qualified the testimony as not being supported by “evidence in the field.” Notwithstanding the prevailing belief in the field, the FDA found it to be misleading for GEH to advertise, based on the NEPHRIC results (comparing Visipaque to one LOCM, Omnipaque), that “Visipaque is safer than other conventional non-ionic contrast media.” (P1894).

This implies that the FDA did not believe that there was sufficient support to conclude that all LOCM perform similarly. Thus, the FDA questioned, based on the NE-PHRIC study, claims of Visipaque superiority over ah LOCM as opposed to merely the LOCM tested in NEPHRIC. GEH relies on several scientific studies to support its claim that Visipaque is less nephrotoxic than other LOCM, and hence has a better renal safety profile, but primarily, GEH relies on the Chalmers and NEPHRIC studies.

Chalmers, first published in 1999, was a randomized head-to-head trial of Visipaque (iodixanol) and Omnipaque (iohexol) administered to patients with RI. It showed Visipaque to be less nephrotoxic than Omnipaque. NE-PHRIC was a double-bhnd, randomized, multi-center, head-to-head trial comparing the nephrotoxicity of Visipaque and Omnipaque in patients with RI and diabetes. Dr. Aspelin was the principal investigator (“PI”) for NEPHRIC. He has nearly 200 published papers and is a peer-reviewer for several journals. Dr.

Aspelin was not a consultant for'GEH and was not paid for his work on the NEPHRIC study, however, he did receive input from GEH regarding the formulation of the language used in his conclusions in NEPHRIC and indeed, GEH was the financial sponsor for the study. NEPHRIC reported that Visipaque was less nephrotoxic and caused 11 times less CIN than the studied CM, Omnipaque. Dr. Aspelin had overall responsibility for, and final authority over, the content of NEPHRIC. The other NEPHRIC authors, including Dr. Berg (a renal physiology expert) contributed to and approved the contents of the

article While the results of the NEPHRIC study, which was a head-to-head comparison of Omnipaque and Visipaque, provide reasonable scientific support for the claim that Visipaque performs better than Omnipaque in high risk patients, it does not support the claim that Visipaque performs better than all LOCM for that patient group. See infra pp. 132-39. Other studies in the field and referred to at trial will be reviewed below. a.

The RECOVER Study RECOVER was a randomized blinded head-to-head clinical trial, published in 2006, comparing the nephrotoxicity of Visipaque and Hexabrix (ionic low osmolar CM) in patients with RI. It showed that Visipaque was less nephrotoxic and caused less CIN than Hexabrix, Neither party, Braceo nor GEH, was involved in the study or publication of RECOVER. Braceo alleges that RECOVER is unreliable due to a discrepancy with an earlier published abstract.

However, the RECOVER authors explained in a published letter to the editors that the published results in the Journal of the American College of Cardiology (herein “JACC”) were accurate, and that the results reported in the earlier abstract were based on preliminary data. Accordingly, the Court finds this study to support the contention that Visipaque is less nephrotoxic than Hexabrix. b. The Jingwei Study Jingwei was a head-to-head clinical trial, also published in 2006, comparing the nephrotoxicity of Visipaque and Isovue in patients undergoing percutaneous cardiac intervention (“PCI”).

It showed that Visipaque caused smaller SCr elevations. Nonetheless, there was no clinically significant difference in the occurrence of CIN. The record does not indicate any involvement by GEH or Braceo in the Jingwei study. c.The McCullough Meta-Analysis (“MA”) The McCullough Meta-Analysis (“MA”), published in 2006, used patient level data from head-to-head randomized intra-arterial clinical trials gathered from a GEH patient database. Dr. Peter McCullough, a consultant for GEH, and co-authors had control over the MA McCullough found that Visipaque was less nephrotoxic than LOCM in: (

i) all risk level patients; (ii) patients with RI; and (iii) patients with RI and diabetes. Bracco’s expert, Dr. Lee Jen Wei, re-analyzed the MA and confirmed that Visipaque causes less CIN than the LOCM analyzed in the study using the CIN definition chosen by McCullough. However, as Wei cogently and significantly pointed out during his testimony, the McCullough MA was comprised of 16 studies, 9 of which were Omnipaque and 7 of which were non-Omnipaque LOCM. Isovue only represented 1 of the 16 studies. Dr.

Wei concluded through statistical analysis, and the Court finds his testimony credible and persuasive, that when the non-Omnipaque studies were compared to Visipaque there was no statistically significant difference in CIN and that the nine Omnipaque studies skewed the results. Therefore, the Court does not find the McCullough Meta Analysis Study reliable for the claim that Visipaque (“IOCM”) causes less CIN than all LOCM. d.

The VALOR trial The VALOR study, sponsored by GEH, was an head-to-head clinical trial comparing the nephrotoxicity of Visipaque and Optiray, and allowed for the discretionary administration of Nacetylcysteine (“NAC”). Following a protocol specified interim analysis, it was determined that patients receiving NAC had more CIN. Thus, enrollment was suspended and then terminated. A manuscript reporting on VALOR was submitted for publication in 2007. The incidence of CIN was lower with Visipaque than Optiray, and Visipaque caused a lower maximum percentage change in SCr from the baseline.

However, the study concluded that there was no statistically significant difference in the incidence of CIN between the two CM tested; therefore no reliable conclusions can be drawn from this study as to Visipaque’s renal superiority. e. The IMPACT

article IMPACT was a study sponsored by Braceo and completed in 2006. It was not a prospective study, but combined secondary data from two previously completed Braceo studies, INVICTA and VIR-PACT, that were designed to study image quality, not CIN. The post-hoc combination of data from two studies was not disclosed in the manuscript and is not an accepted practice in the scientific community. Although Dr.

Feldman testified that IMPACT does not contradict the conclusions of NEPHRIC because of the different patient sample groups, IMPACT does come to the conclusion that Visipaque and Isovue performed similarly and had similar renal safety profiles in patients at elevated risk for CIN. f.The CARE Study CARE was another Braceo sponsored study comparing Visipaque and Isovue. CARE was published in May 2007, and, prior to that, was not available to GEH. All patients received sodium bicarbonate according to a protocol from the Merten study, which showed that sodium bicarbonate reduced CIN when used with Isovue.

Merten concluded that sodium bicarbonate inhibited the negative effects of hyperosmolar stress caused by LOCM such as Isovue. At the time the CARE protocol was finalized, there was no significant evidence that bicarbonate was beneficial when used with an iso-osmolar agent like Yisipaque. Dr. Feldman testified that CARE does not speak to the relative nephrotoxicity of Yisipaque and Isovue without use of bicarbonate and does not contradict Chalmers, NEPHRIC, RECOVER, Jingwei, or the McCullough MA.

That is true, however, the Court finds this study’s findings probative because its results indicate no statistically significant difference in CIN between Isovue with sodium bicarbonate and Visipaque with sodium bicarbonate. g. The Sharma Pooled Analysis, Solomon Systematic Review and Solomon/DuMouchel articles are biased and methodologically flawed The Sharma Pooled Analysis (D262A) was drafted in-house by Braceo and was based upon a prior

article by Dr. Alberto Spinazzi, Bracco’s senior vice-president responsible for medical and regulatory programs. Braceo performed the statistical analysis and paid Dr. Samin K. Sharma, a doctor at Mount Sinai School of Medicine, $50,000 for his costs associated with the article. Braceo also drafted the Solomon Systematic Review (D107) and paid Dr. Richard J. Solomon, a specialist in internal medicine and nephrology and an expert proffered by Braceo, $30,000 for his involvement. Together with Dr.

Solomon, Braceo published an abstract of its review, but without data from Chalmers to “strengthen the argument” of equivalency between Isovue and Visipaque. Braceo and Dr. Spinazzi were intimately involved in drafting the Solomon/DuMouchel

article (D222). Because of methodological flaws, the Court finds that no reasonable conclusions on the relative nephrotoxicity of Visipaque, Omnipaque and Isovue can be drawn from the Sharma, Solomon Systematic Review or Solomon/DuMouchel articles. Bracco’s expert, Dr. Isabel Elaine Allen, attempted to validate the Solomon Systematic Review, but her analysis was plagued by errors. The reported CIN rates in both Solomon and Sharma were in fact lower for Visipaque than for both Isovue and Omnipaque, although the difference in the rate of CIN between Visipaque and Isovue was not statistically significant.

There was a statistically significant difference in the rate of CIN between Visipaque and Omnipaque, and furthermore a statistically significant difference between Isovue and Omnipaque; Visipaque and Isovue performed better than Omnipaque overall. h.

The NEHPRIC Study The NEPHRIC study, reported in the NEJM (P2467), compared Visipaque and Omnipaque head-to-head, but stated in its conclusion that “[njephropathy induced by contrast medium may be less likely to develop in high-risk patients when iodixanol [ (an iso-osmolar contrast medium) ] is used rather than a low-osmolar, nonionic contrast medium.” Braceo assails the reliability of the NEPHRIC study by contending: (1) it was not designed to test whether osmolality is responsible for CIN (e.g., 20 T 6) and therefore cannot support the conclusion that Visipaque performs better than all LOCM in connection with renal function and CIN; (2) it has never been repeated in an AWC study; (3) it does not provide any support for the conclusion that Visipaque is as good as or better than LOCM with prophylactics; and (4) it does not represent the weight of scientific evidence. (P2467; 3 T 89-90).

In addition, Braceo avers, through the testimony of Dr. Solomon, that Table IV of the NEPHRIC article, which purports to present results from other studies, is inaccurate and misleading because it incorrectly reports the results of those studies. (3 T 126-31; P3148, 37, 2053, 2386, 2390). Braceo also alleges that Table IV is inaccurate and misleading because it does not report the allegedly contradictory results of GEH’s NEPHRIC II study; but NEPHRIC II was not completed prior to the publication of the original NEPHRIC

article and therefore could not have an impact on the reliability of the Table IV charts when published. Additionally, any such allegations as to the results of the NEPHRIC II study are speculative and it is improper for the Court to draw any inferences in the absence of its production. According to Braceo there are several additional flaws inherent in NEPHRIC which make it unreliable: • Primary outcome flaw. The record indicates that Nephric’s primary endpoint — mean peak change in serum creatinine — is not a reliable metric, although it is used in the

article and GEH’s ads (e.g., the 11 times better assertion). (33 T 207) (Feldman). P4288:437 (“unknown clinical significance”), P200 (p3, FDA rejects Nephric’s mean peak change endpoint); see also P1540 (definition of clinically significant) • Omitting of key results. The NEJM

article does not report the 25% rise in serum-creatinine results (P44, P4144, P1887; D2039T), which GEH added to make the study more comparable to the Chalmers study and to provide a more rigorous test for CIN. Id.; 3 T 90-99. Instead, the

article falsely states that the secondary endpoints were significantly better. (P2467:913). GEH’s marketing director was aware of this unreported data (e.g., P195L131 (declining to provide the 25% results in Spain)) and he permitted the

article to falsely report that all of the secondary outcomes showed a statistically significant (defined as p<0.05) difference between Visipaque and Omnipaque • Hydration flaws. Inadequate hydration was described by a GEH doctor as one of the “greatest weaknesses of the study” but it was not acknowledged in the

article or any ad. (P530:148, 20 T 25; 3 T 101-105). • Baseline and other population flaws. The patients in the Omnipaque group had worse baseline values (P207-08, P979, P1887, P48, P49; 3 T 119-120; 20 T 35), which greatly increases the chance of getting CIN. Id. The patient groups also had other differences that were never analyzed together. Id.; 3 T 105-109,112-117. Furthermore, since there was no standard hydration, and hydration changes baseline values to an unknown extent, there is no way to know the correct values and thus there was no way to accurately calculate mean peak change or CIN.

P823, P4250; 20 T 39. • Improper manipulation. While the study was ongoing, and in violation of the protocol and proper practice, GEH took secret and forbidden peeks at the data looking for trends, and even changed the study endpoints and stopped the study early in response.

E.g., P562:821 (found “Mean of max day 2 and 3: 20% (25% for Omnipaque and 15% for Visipaque)” to compare treatment arms before study completion), 1882:966 (“The statistician thought the data [from the two treatment arms] looked equal in both CrCl groups.”); 11 T 20-26, 43-44, 71-75; D2039T (“pretend”, “plausibility will not increase”), 2339, 2440. These types of unplanned interim analyses (defined by D2340:42 and D2339:34 as any comparison of treatment arms prior to completion) and secret attempt to “fix” the study midstream makes the trial non-prospective. P830; 20 T 28-33, 11 T 14-44, 70-71; P130.

When a NEJM reviewer asked whether there was an interim analysis (P1869, 46), GEH and the authors replied there was none, and then amended the

article to falsely say there was none. (P68; 20 T 17-18). • Hidden duration of diabetes flaw. Duration of diabetes may be a predictor of CIN (P 4377:29K; 34 T 57-62). GEH found that the statistically significant higher duration of diabetes in the Omnipaque patients may explain the results, independent of the CM, making the conclusion of the

article unreliable. GEH did not reveal these results to the public. (P49, P967, P4364, P4364T, P4365, P4365T; 20 T 33-34). • Misrepresentative conclusion and manuscript. GEH’s marketing director provided input to the NEJM

article to try to make it misleading, and then celebrated the final version’s obscuring of the limitation of the results of the study to Omnipaque and its overly broad and unsupportable conclusion. P1519, P1534, P1535, P4210 (admitted to only show input), P1532, P4208, P1672, P1873 (conclusion same as TCT abstract), P1876, P4208; 6 T 87-89, 13 T 62-71; see also P480. (PL’s FOF ¶ 13). Taking into consideration that the study compares one LOCM (Omnipaque) with Visipaque, nonetheless, the Court does not find that the study’s results are vitiated by the flaws identified by Braceo.

In addition, the NEPHRIC study uses conservative language in its conclusion (e.g.-use of Visipaque “may” cause less CIN than “a” LOCM), which does not render the study unreliable merely because it only compared Visipaque and Omnipaque.

As it pertains to GEH’s advertising, however, the non-definitive language used in the NEPHRIC conclusion permits GEH to use it for the contention that Visipaque may be renally better than a LOCM (which in the context of the article, means better than Omnipaque), but only if GEH plainly identifies, in same size print (and not in footnoted material), that Omnipaque was the only LOCM compared and that the NEPHRIC findings are limited to the studied CM. The NEPHRIC

article cannot be used to claim that Visipaque has a superior renal safety profile to all or any other LOCM. Further, in regard to the claim that “Visipaque is as good as or better than LOCM with prophylactics,” the Court finds that the results of the NEPHRIC study cannot reliably support such a conclusion because using a LOCM with prophylactics was not part of the results of the study and was only concluded through a MA.

Moreover, Braceo contends that reliance on NEPHRIC is unreasonable because all other reliable clinical trials, reviews and MAs demonstrate no basis for a superiority claim of Visipaque over Isovue. Indeed, Braceo contends that all reported AWC clinical evidence and properly conducted MAs (e.g., Dr. Wei’s unrebutted MA of GEH data) show no statistically significant difference between Visipaque over either Isovue or Optiray, whether given i.a. or i.v. (1 T-4 T, 11-12).

Braceo also contends that for seven years prior to the NEPHRIC campaign, no doctors had ever observed that Visipaque caused less CIN, Id., and that GEH’s internal hidden data, never mentioned in its ads, also show no renal superiority for Visipaque. GEH reported to its representatives that the studies provide valid and reliable information and that anecdotal experiences are not reliable in making CIN comparisons. (P260:413; 13 T 72-74). In further support of its claim for false advertising, Braceo also relies on FDA findings which declined to approve a renal superiority claim for Visipaque.

The FDA has repeatedly found (e.g., in the years 1996, 2001, 2005) that there is inadequate support to make renal superiority claims for Visipaque. (E.g., P596, P457, P585, P200, P816, P1894; 7 T 54-56; 14 T 41-57; 15 T 25-37, 38-39, 43-48). Furthermore, in 2001, GEH submitted the proposed NE-PHRIC study to the FDA with proposed superiority claims. (P200, P199, P4205, P816, P556, P818, P1542, P264B, P271, P1670, P1543, P810, P972; 20 T 48-57; 14 T 57-62).

The FDA again rejected GEH’s proposed claims, requiring AWC clinical trials and rejecting NEPHRIC as an AWC clinical trial (e.g., “the current [NE-PHRIC] protocol contained a number of sources of variability, which may confound the ability to clearly determine the effects of the drug on renal function”). (P200, 1542; 20 T 48-51). As part of GEH’s rebuttal to the assertion that its representations constituted false advertising, GEH relied on four studies; Chalmers, NEPHRIC, RECOVER and the McCullough MA. Braceo contends that flaws in these studies vitiate their results as follows: (

a) Chalmers was not AWC (small and unblinded), showed no significant difference (there was total agreement that the 10% test is irrelevant), and even the authors concluded it was weak (3 T); (

b) NEPHRIC is unreliable; (

c) RECOVER only involves Hexabrix (an ionic agent), it showed no differences in certain CIN measures and it is unreliable (3 T; Solomon Dec.; D1990; P3823); and (

d) the McCullough MA is of limited value as demonstrated by Dr. Wei’s unrebutted testimony (11 T-12

T) that the McCullough MA results were mostly due to Omnipaque (and not Isovue). The Court finds that these studies’ conclusions do not establish the proposition that Visipaque has renal superiority to all LOCM. Turning specifically to the NEPHRIC study, despite certain flaws, there were significant reliable aspects. The Visipaque and Omnipaque groups in NEPHRIC were demographically comparable. The requisite number of patients pursuant to the protocol were included. All patients had RI and met the inclusion criteria.

Also, the Court is not convinced that the use of NAC in 11 patients affected the viability of the NEPHRIC results. Furthermore, contrary to Bracco’s assertion, no interim analysis, as that term is understood and defined by the scientific community, was performed during NE-PHRIC. ICH and FDA Guidelines for clinical trials, adopted by Bracco’s expert Dr. Sanford Bolton (an expert in pharmaceutics, physical pharmacy and bio-statistics, as authoritative), define an interim analysis as the unblinded comparison of treatment results. During NEPHRIC, the results were not unblinded and treatment results were not compared.

ICH and FDA Guidelines acknowledge that a sponsor may, without impacting a study’s validity, monitor the success of planned accrual targets and the appropriateness of design assumptions. Indeed, it is the sponsor’s responsibility to do so. Thus, GEH’s monitoring of patient enrollment, sample size assumptions and overall (not separated into two treatment groups) SCr changes (e.g., Ps 562, 1882, 1883, 1884, 1885 1890, 1891), do not constitute interim analyses. As to Bracco’s claim that GEH influenced the wording of the NEPHRIC study conclusion, the Court finds that GEH did have input. Nonetheless, Dr.

Aspelin’s first draft dated March 6, 2002, which was authored before GEH offered comments and before presentation of an abstract at the TCT conference, also included a conclusion applying NEPHRIC results to the class of LOCM. Further, Dr. Aspelin testified that he, his co-authors, and the New England Journal of Medicine editors believed in the scientific reasonableness of the conclusion. All of this lends support to the reliability of the article, but combined with the chronic rejection by the FDA of its use for superiority advertising and the fact that the NEPHRIC

article only compares one LOCM to Visipaque, it cannot be concluded from the study and the

article that Visipaque is renally better than all LOCM. Indeed, this latter finding is also supported by the non-definitive language used in NEPHRIC’s own conclusion that Visipaque MAY cause less CIN than A LOCM.

Thus, the Court concludes that the NEPHRIC results do not support a claim of Visipaque renal superiority over all LOCM or any LOCM other than the one tested in that study (Omnipaque) because only one LOCM was compared, and because the NEPHRIC conclusion does not make an absolute claim of Visipaque renal superiority, hedging its findings with less than definitive language; NEPHRIC also does not support a conclusion that Visipaque has renal superiority over LOCM with prophylactics because the study did not compare any LOCM with prophylactics against Visipaque. i.

None of the Proffered Studies Demonstrate that all LOCM (including Isovue) without Prophylactics Cause the Same Rate of CIN Braceo contends that P1937, an internal GEH document with MA results, shows differences in rates of CIN between LOCM and that as such, a head-to-head study with one LOCM cannot be extrapolated to other LOCM. GEH contends that this was not an analysis of relative CIN rates and that published guidelines treat all LOCM, including Omnipaque and Isovue, as functionally interchangeable.

However, the Court finds that even though multiple CM are categorized together as LOCM, it does not mean that they have the same effect, or produce the same rate of CIN. The Court is not persuaded that all LOCM perform identically — multiple studies introduced in evidence show that not all LOCM perform similarly nor do they produce the same rate of CIN. (See RECOVER, Jingwei, McCullough MA, VALOR, IMPACT and CARE). 3.

GEH’s Establishment Claims Of Non-Renal Superiority GEH also disseminated establishment claims of cardiovascular system, pain, warmth, discomfort and patient movement superiority, and establishment claims that Visipaque, and iso-osmolar agents generally, are a superior class of drugs that lead to lower hospital, legal and patient care costs. The Court finds that these claims explicitly or implicitly assert that data from clinical studies show that Visipaque is superior to a LOCM or all LOCM and thus they are establishment claims. As with the renal establishmenf/superiority claims, these claims were: (

a) designed to be disseminated (Pl.’s FOF ¶ 4); (

b) shown to be effective by GEH’s collective experience and marketing research (PL’s FOF ¶ 4); (

c) disseminated by the GEH representatives (PL’s FOF ¶ 5); and (

d) disseminated in various channels of communication. a.

GEH’s Non-Renal Cardiovascular Superiority Claims Are Not False And Misleading Examples of the cardiovascular system establishment/superiority claims extracted from GEH’s print media, sales calls records and CME-type presentations are: • Press releases on website even during trial: “Abstract Shows Significantly Lower Incidence of [Major Adverse Cardiac Events or Major Adverse Clinical (“MACE”) ] Following [PCI] Using Visipaque Compared to Isovue.... ” P2669:480, P3114H:857-58, P1893:94041, P4151:p2; 7 T 69. • CT brochures: “Nonionic Dimer Provides Reduced MACE ...” P410:965, P3649:408, P3649A408, D2324:117. • Sales call records: “Visipaque doesn’t increase heart rate or B/P like LOCM”.

P3682: Omni/38573, 4049:Omni/38573. i. MACE Braceo contends that GEH’s cardiovascular claims are false because: (

a) the studies do not support the claims (e.g., no superiority over all LOCM, i.a. results do not predict i.v. results, and any difference purportedly shown in studies was fleeting because the results for different contrast agents converge after 30 days); (

b) there were allegedly omitted results and flaws that contradict the claims made in GEH’s advertising; and (

c) the studies GEH relies on (COURT and VICC) are unreliable. The following is a detailed analysis of Bracco’s allegations beginning with the various promotional materials disseminated and moving on to the integrity of the COURT and VICC trials.

Bracco’s assertions, include: (1) the weight of the clinical evidence shows that Visipaque is not superior to all LOCM and definitely not superi- or to Isovue (Braceo concedes that ionic Hexabrix may be inferior); and (2) there has never been one AWC clinical study (let alone two, done the same way with the same drug) showing that Visipaque is superior to a LOCM with regard to MACE. 1. FDA findings Referencing a series of letters dating back to 1996, Braceo argues that the FDA found no support for GEH to make cardiovascular superiority claims. (E.g., P596, P457, P588, P585, P82; 15 T 25-39, 43-44).

Nonetheless, some of these letters predate the COURT trial (circa 2000) and all pre-date the VICC trial (circa 2005) and since that time, new evidence has come to light. Thus, the Court finds these FDA letters are neither dispositive, nor highly probative as to whether GEH’s advertising was literally false regarding its claims of the incidence of MACE. See infra pp. 467-69. 2. COURT Study as Reported by GEH Braceo asserts that GEH reported false information from the COURT study. (P2561). According to Braceo the study is limited to: (

a) a comparison between Visipaque and ionic Hexabrix; (

b) the patients studied (“extrapolation of these results to [a stable] population is not possible” (P2561), and the reported results were not consistent with the results from the less sick patients in the VIP study, see discussion infra at pp. 417-18, (P71)); and (

c) a fleeting difference in adverse events between the two drugs cumulatively at the 30 day point (something not mentioned in GEH’s ads). (5 T 37-44). Braceo also asserts that the actual data, including data not disclosed by GEH, show that there were no differences between the drugs and the results were not reliable. GEH responds by contending that COURT was a randomized head-to-head clinical trial comparing Visipaque and a LOCM, Hexabrix, in 856 high risk patients undergoing Percutaneous Transluminal Coronary Angioplasty (“PTCA”). Dr. Davidson was the principal investigator (“PI”) and helped design and run it.

Dr. Kevin Harrison, the PI of the Braceo sponsored VICC trial, was also an investigator for COURT. The primary endpoint of COURT was in-hospital MACE. The in-hospital period is most relevant because MACE events caused from CM, as opposed to those caused by other factors, tend to cluster in the first few days. The Visipaque group had less in-hospital MACE than Hexabrix (5.4% vs. 9.5%) and fewer myocardial infractions (“Mis”) (2.0% vs. 4.4%). The incidence of MACE at 30 days favored Visipaque (9.1% vs. 13.4%). Dr.

Kern, a Braceo expert, agreed that COURT showed that “the incidence of [MACE] and major angiographic complications are reduced in high risk patients undergoing coronary interventions with Visipaque compared "with Hexabrix.” MACE events in COURT were adjudicated in a blinded manner by the authors. I need not find whether the COURT results could support a conclusion that MACE is related to osmolality, because the conclusion in COURT only stated that Visipaque causes less MACE than Hexabrix in high risk patients undergoing coronary intervention.

The Court finds that, despite the qualms referenced by Braceo, the COURT study is sufficiently reliable to permit one to conclude with reasonable certainty that it established a cardiovascular superiority claim for Visipaque over Hexabrix for use in high risk patients undergoing coronary intervention. COURT does not, however, support such a conclusion as to any LOCM other than Hexabrix. 3. VICC study The Bracco-sponsored VICC trial compared Isovue to Visipaque. (P2326, P3909).

However, this study has never been published in a peer-reviewed journal and Braceo contends that it was poorly designed and unreliable based on several flaws, including: (

a) its crossover effect and lack of a washout period, (23 T 122-124); (

b) its failure to uniformly measure CK-MB (23 T 126-127); (

c) its side effect; and (

d) the adjudicators’ failure to follow the rules on calculating CK-MB change (P3912:654). D1441; 5 T 44-67; 25 T 121-44; 33 T (Spinazzi). The Court finds that these concerns, whether in isolation, or in conjunction, do not make the study so unreliable as to render it unsupportable for the conclusions stated therein. The results of the trial show that Visipaque had statistically significant less incidence of in-hospital MACE than Isovue. GEH correctly avers that VICC was a Braceo sponsored head-to-head randomized trial comparing Visipaque and Isovue in 1276 patients at mixed risk levels for MACE. Dr.

Harrison was the PI. Drs. Charles Davidson and Morten Kern were co-investigators. The idea for the VICC trial came from Duke University, which approached Braceo for support. The evidence reveals that Braceo agreed to sponsor it and then tried to minimize publication of any negative results. The primary endpoint of VICC was the incidence of MACE in the earlier of the first two days following contrast administration, or until hospital discharge. The VICC protocol specified CK-MB for the primary diagnosis of non-Q-wave Mis. CK-MB are commonly used in clinical practice for such diagnosis.

Visipaque caused less in-hospital MACE than Isovue (4.8% vs. 9.0%), including less in-hospital non-Q-wave Mis (3.4% vs. 7.5%), which the study concluded was significant for treatment. At 30 days there were significantly fewer non-Q-wave Mis with Visipaque. The periods of 0-7, 2-7, and 2-30 day MACE were included as secondary endpoints in VICC, but are not as clinically relevant as in-hospital MACE. There was also no significant difference in repeat PCIs of the target vessel, i.e., the vessel treated at the time of procedure. Repeat PCIs of non-target vessels are unlikely to be related to the effects of CM.

The Court finds that it is scientifically reasonable to conclude from VICC that

(1) Visipaque is associated with significantly less in-hospital MACE than Isovue; and

(2) Visipaque is associated with fewer non-Q-wave Mis than Isovue. The primary results of VICC and COURT are essentially the same. VICC confirmed the findings of COURT, extended it to a different comparative agent, and was a more contemporary study based on the practice having changed, i.e., use of more stents and the use of more IIB/IIIA inhibitors. Dr. Kern testified that the lack of a washout period in VICC makes the data difficult to interpret, but Dr. Harrison disagreed; he testified that it does not affect interpretability of the data. In addition, Dr.

Davidson testified that he did make sure that the patients in his portion of the VICC trial who underwent a diagnostic procedure got the same drug as in the interventional procedure, thus eliminating a crossover or a washout effect. (23 T 122:24-123:14). Furthermore, he found that Visipaque performed better than Isovue whether it was the same contrast agent being used in the procedures or whether there was contamination from another contrast agent. (23 T 123:18-124). Further, Dr. Kern signed the published abstract that did not mention the washout issue and approved the protocol in conjunction with his colleagues.

The testimony reveals that Braceo believed VICC favored Visipaque, and thus would damage Isovue in the market. As a result, Braceo sought to contain damage by re-analyzing the data, seeking to undermine the validity of unfavorable results, and pressuring Dr. Harrison regarding the contents of the abstract and manuscript. The Court finds that the VICC study is sufficiently reliable to permit one to conclude with reasonable certainty that Visipaque causes less in-hospital MACE than Isovue for patients undergoing PCI within the initial 48 hours after the procedure. 4.

The VIP Trial The Court finds that VIP, a study published in 2000, that compared Visipaque and Hexabrix in low risk patients, does not undermine the conclusions of COURT or negate its findings regarding high risk patients. However, VIP’s conclusion that there is no statistically significant difference between Visipaque and Hexabrix in low risk patients with regard to MACE, militates against any finding that Visipaque performs better than this low-osmolar contrast agent with regard to MACE in that patient group.

Furthermore, since no other studies have focused on Visipaque and any other LOCM to confirm the incidence of MACE in low risk patients, there is no basis to assert any Visipaque superiority claims for MACE in low risk patients. ii. Hemodynamic Effects Braceo contends that GEH has not rebutted Bracco’s evidence that iso-osmolality and Visipaque are not superior over Isovue or other non-ionic LOCM for heart rate, blood pressure, ECG, LVEDP and other cardiovascular effects as shown by Dr.

Kern and VIP (P71), IMPACT (P2799), Sutton I (P3770), Sutton II (P3855), Verow (P2356), Manninen (P3846), Palmers (P3847), and Klow (3844), or that iso-osmolality does not cause less red blood cell deformity than LOCM. 5 T (Kern); P27, P34, P41; 2 T (Katzberg). Moreover, GEH’s internal data also shows no superiority: DXVPRC01 (P1705); DXVD09 (P220:931). (5 T 76; 2 T 58-60). Braceo contends that GEH’s rebuttal ignored Bracco’s proofs and relied on excerpts from three articles that are not cited in the ads in issue and that cannot support the scope of its claims: the Bergstra

Article does not attribute the LVEDP difference seen between Omnipaque and Visipaque to osmolality differences (D814:222) and the Soiva and Murdock articles did not involve Visipaque (D2249; D2377). In fact, Soiva, finding significant differences between LOOM, showed that LOOM cannot be considered as a uniform group. Here, GEH incorrectly contends that there is a good basis to conclude, from clinical trials, that Visipaque causes fewer and milder hemodynamic effects {e.g., heart rate changes) than LOOM and that LOOM are all similar in this regard.

The Court finds that these conclusions are neither adequately supported nor reliably based upon the studies GEH cites. b.

GEH’s non-renal discomfort-type claims Examples of the discomfort-type (i.e., claiming less pain, warmth, discomfort or patient movement or designed for such) establishment/superiority claims extracted from GEH’s print media, sales calls records and CME-type presentations are: • Website, brochures and CMEs: “[Visipaque] offers significantly better comfort to the patient ...” P2508:767A, P2511C:781A, P4163:767A, P4166C:781A. • CT brochures: “Less chance of extravasation-related complications — including pain, discomfort ... when used:” “Less chance of patient discomfort ... when used in:” “High concentration”, “High-rate injections”, “Multiple procedures”, “High-speed procedures.” P410:966. • Sales call records: “She asked why use Vis Shared theory iso-osmolar, less fluid shifts and thus less pt discomfort, movement and need to rescan.... ” P2312:A650688, P4049:A650688.

GEH makes claims that Visipaque is superior to LOOM because it provides less pain, heat, and discomfort and that these benefits are due to its iso-osmolality. Braceo contends that these claims are false and misleading because: (

a) the studies do not support the claims {e.g., no superiority over all LOOM, i.a. results do not predict i.v. results, no difference in movement ever shown); (

b) omitted results and flaws contradict the statements; and (

c) the weight of the clinical evidence is that Visipaque is not superior to all LOOM and definitely not superior to Isovue. There may be a benefit in heat sensation that is sometimes described as pain in peripheral angiography, but that has never been proven and peripheral angiography is a de minimus use of CM. (1% today, 2 T 91; 29 T 158-159). GEH’s own Dr.

Anthony Nicholson, an interventional radiologist, testified that GEH’s claims were too broad because any benefit of Visipaque is limited to direct local injections in small vessels, a limitation found in none of GEH’s advertising claims. (Id.) In addition, there has never been one AWC clinical study that was repeated and supports the claim that Visipaque is superior to a LOCM (or all LOCM) in a manner claimed by GEH. Furthermore, Braceo contends that the FDA found there was no support to make discomfort-type superiority claims for Visipaque. (E.g., P596, 457, 588, 585, 82; 15 T 25-39, 43-44).

At most, the FDA permits GEH to make a very limited and inconclusive statement about a trend that is not a superiority claim. (14 T 66). There have been eleven studies showing no difference in patient movement and no reliable study showing a difference in patient movement. GEH’s attempt to show a difference (DXV071) was a failure so GEH did not make great effort to release the results. (P557). Furthermore, data from unpublished studies showed no consistent differences in pain, discomfort or movement: GEH MA (P549); DXV071 (P557); DXVA001 (P220:930); DXASG001 (P220:930); DXVD11 (P220:932); 2 T.

Braceo asserts that Dr. Michael Rappeport’s survey demonstrated that the claim, Visipaque is superior regarding pain “compared to LOCM”, is understood by an overwhelming proportion of customers to claim superiority to all LOCM. (PL’s FOF ¶ 18). However the Court is excluding Dr. Rappeport’s survey for its inherent unreliability. See infra p. 90. In response to the Rappeport survey, GEH proffered Dr.

Nicholson who presented several studies asserting differences in pain or discomfort (nothing on patient movement) but none compared Visipaque to all LOCM or even one LOCM in an AWC study that was ever repeated. (See 29 T). Conversely, GEH avers that CM can cause pain, discomfort or heat upon injection, and that this aspect of patient comfort is clinically relevant. GEH also contends that Visipaque causes less pain, discomfort and warmth than LOCM, including Isovue, in certain procedures, and that this difference is clinically relevant. No study has shown Isovue to cause less pain than Visipaque.

Braceo acknowledged that there is less pain with Visipaque than Isovue in peripheral angiography procedures. Bracco’s expert, Dr. Katzberg, acknowledged the same. Furthermore, GEH’s expert, Dr. Nicholson, could not substantiate by a reasonable degree of scientific certainty, based on the studies, that any claim of Visipaque superi- or regarding pain extended beyond peripheral angiography procedures. Accordingly, the Court finds that GEH’s claims of comfort superiority are only supported in regard to peripheral angiography procedures.

Thus, GEH’s broad assertions of superior patient comfort are not supported by the conclusions of the various studies it uses to bolster them and any such advertising must be limited to the procedures that were used in the studies. c. GEH’s Osmolality Class/Cost Claims Examples of the osmolality class and cost establishment/superiority claims extracted from GEH’s print media, sales calls records and CME-type presentations are: • Website: “Isosmolar Visipaque.

It’s innovative in a class of its own.” P2505:757A, 2511A:774A, 4155A:737, 4160:757A, 4166A:774A, 3448A:p2 • Diagrams/claims repeated in websites, brochures and CMEs: Showing “hyperosmolality” (i.e., osmolality higher than blood, like Isovue) leading to “altered morphology” of “erythrocytes” and “endothelial cells”, ultimately leading to “discomfort”, “warmth”, “coldness” and “pain.” P2508:766A, P2511C:781A, P4163:766A, P4166C:781A; see also P3114K:823, P2510:771A, P2508:763A, P2511C:779A, P4163:763A, P4165:771A, P4166C:779A, P2183:982, P2184:000, P2311:p4, P2298:p25, P4252:p3, P3828:929, P3261:011, P3829:036, P2156:036, P2157:212.

Additional claims of less red blood cell effect of IOCM vs. LOOM can be found at: P2311:p5, P3710:p2, P2280:p5, P395:357, P409:945, P333:738, P410:960, P3649:403, P3649A:403, P436A:421, 27-28, P2298:p7, 13-14, P782:893, P216L387, P2183:991, P2184:009, P4252:pl2, P4174:pl, P3114J:821, P3210:934, 410:962, P3649:405, P3649A:405, P2510:772A, P2508:764A65A, P2511C:780A, P4163:764A-65A, P4165:772A, P4166C:780A; D2324:114, D2334:p2, D2324:112 • Health Value brochure: “Isosmolar VISIPAQUE may reduce financial burden due to serious adverse events”.

P446:641, P649;665 • Sales call records: “Used the ‘cost’ story for Visi vs. LOCM” P3682:Visi/154349, P4049:Visi/154349 These claims are based upon alleged renal, cardiovascular or discomfort-type superiority tied to osmolality (e.g., 6 T 94-99) or costs. Braceo asserts that they are false and misleading because (

a) the studies (shown above) do not support the claims (e.g., no superiority over all LOCM, i.a. results do not predict i.v. results), and (

b) omitted results and flaws contradict the claims. The Court finds that the weight of the clinical evidence does not show that Visipaque is superior to all LOCM nor does it show that it is superior over Isovue, except perhaps under limited circumstances for pain and in-hospital MACE for patients undergoing PCI. The FDA found that there was no support for making class/cost superiority claims for Visipaque. (E.g., P588, P585, P82; 15 T 33-39, 43-44).

Furthermore, GEH’s medical officer testified that while iso-osmolality is a chemical property of the final Visipaque formulation, it does not put the drug in a proper, formal class of drugs separate from LOCM by FDA standards. (16 T 186-187) (“IOCM and LOCM are not separate classes, Correct?” “That is true.”). This is because the FDA classifies all iodinated contrast media the same. (Id.) In addition, Braceo contends that GEH improperly advertised the role of osmolality in causing adverse events.

GEH’s documents give some indication that Visipaque has a much higher rate (5-7 times) of delayed adverse events than Isovue and other LOCM (e.g., P1948:947(1.4% v. 0.2%), P2133, P1169, P544, P557, P3860:167; 13 T 82-85) and thus it belies GEH’s superiority claims in regard to Visipaque (and iso-osmolar Isovist, withdrawn for this reason). In light of this data (P1169:703, P4240:670, P544), GEH countered with claims that there were an equal or lower number of adverse reactions. (E.g., P229L054, 2305(Conclusion), 2309, 976, 2026, 2027, 2286; 15 T 151-152).

GEH also argues that Bracco’s foreign affiliate and experts agree that osmolality is relevant to renal safety, cardiac safety, and pain/discomfort. However, the Court does not attribute significant weight to these general assertions. Finally, Braceo asserts, and the Court agrees, that there is little evidence to support a claim of decreased costs using Visipaque. There is no support for GEH’s claims that studies show that there is less patient care, hospital care or legal liability costs for Visipaque versus all the LOCM or even one LOCM.

The only way to make such a cost inference is by associating the cost of treating additional instances of MACE and CIN to higher overall cost, but since the Court has not made such a finding with regard to CIN, the only viable means of advertising lower cost is through less incidence of MACE for patients undergoing PCI within the 48 hours after the procedure. 4. Additional Evidence Regarding Dissemination In addition to the proofs cited above, dissemination of allegedly false claims was confirmed by the testimony of Mr. Scott Kerachsky, Director of Marketing for GEH Healthcare, North America, (15 T 100-142), Dr.

Peter McCullough (34 T 160-165), and stipulations by GEH. GEH representatives are instructed to present printed materials a

section at a time, by pointing to specific parts, and not as a whole. (E.g., 15 T 116, 172-175; P2100:530, 2098). But, in his testimony, Mr. Kerachsky also elaborated on the impact of GEH’s various levels of approval mechanisms over promotional materials and their dissemination. Specifically, Mr. Kerachsky identified four levels of approval, medical, regulatory, marketing, and legal, whose responsibility it is to ensure that the clinical data provides support for proposed promotional materials. (15 T 86, 90). Mr.

Kerachsky also testified that every piece of promotional material used by GEH’s sales force was approved by medical, regulatory, marketing, and legal. (15 T 83, 86, 90). In fact, Mr. Kerachsky himself reviewed prospective promotional materials from a marketing prospective, mindful of FDA regulatory issues and possible conflicts with the underlying clinical data. (15 T 93, 95, 125). For example, with respect to NEPHRIC, Mr. Kerachsky testified that marketing “clarified, just to be extra careful, that it was iohexol” which was studied. (15 T 125).

For the time period covered by GEH’s sales call record production (i.e., Sept. 2003-2005), Braceo asserts that at least 87% of GEH’s representatives delivered GEH’s clinical superiority claims. (17 T 102,107; 18 T 25-34, 40, 42-43; P3493M, 3922, 4049; D2004).

While Braceo asserts that at least 82.5% of GEH’s sales call records with substantive communications show the delivery of GEH’s clinical superiority claims to customers, the Court finds this number to be grossly inflated based upon its own evaluation of the records and expert testimony; nonetheless, some instances of false messages are supported by the record. (See also 17 T 102, 107; 18 T 25-34, 40, 42-43; P3922, 4049; D2004). GEH argues that Braceo has grossly mischaracterized the number of actionable sales call notes and promotional materials, specifically because of flaws in Mr. Russell’s testimony.

For example, Mr. Russell could not identify the basis for his testimony that certain GEH promotional materials contain pain/discomfort superiority claims. Mr. Russell improperly categorized: (1) accurate discussions of the NEPHRIC study, and (2) a Visipaque logo as renal superiority claims. Mr. Russell could not identify the basis for his categorization of GEH promotional materials, including a specific piece containing the statement “Is your contrast media this close to plasma?” as cardiac superiority claims. Mr.

Russell improperly categorized statements, including “Currently, there is no health care common procedural code to delineate iso-osmolar contrast agents such as Visipaque from low-osmolar contrast media LOCM,” as class claims. Mr.

Russell improperly categorized statements in GEH promotional material, including a piece that expressly states that medical personnel should consider taking prophylactic measures to reduce the risk of CIN, as promotion of “the lack of pretreatments and emergency use without renal function testing.” Nonetheless, a number of the sales call notes reviewed by this Court do indicate that certain members of the GEH sales force were using the NEPHRIC study’s conclusion to make superiority claims. In addition, GEH argues that Mr. Russell’s analysis of sales call notes is unreliable because of the allegation that Mr.

Russell’s compilation of allegedly improper sales call entries was compiled by Bracco’s counsel and was widely over-inclusive. The compilation was created from 314,468 GEH sales call notes produced in this case. For example, Mr. Russell improperly categorized entries that reference only the word, “NEPHRIC,” as being “on-message.” Also many included notes were duplicative. In addition, GEH states that Mr. Russell’s compilation improperly categorized sales call notes as (1) renal superiority messages; (2) cardiac superiority messages; and (3) evidence of the application of Visipaque “leverage.” Indeed, Mr.

Russell admitted that there was no reason that innocuous sales call entries such as “Discussed use of Visi for high risk patients”; “Told him about Visi for the coronary”; and “Thanked Dr. Vogel on the lead to move forward to bundle a LOCM and MRI contrast deal,” were included in the above categories, respectively. GEH argues that due to the lack of standards employed, Mr. Russell’s compilations are inflated and unreliable. The Court agrees that Mr. Russell’s opinions as to the percentage of “onmessage” sales call notes and representatives who made them are greatly inflated.

Nonetheless, the Court has had the opportunity to review the sales call notes and disagrees with GEH that the Court should only review sales call notes that mention Isovue as follows: (1) 284 notes that mentioned Isovue; (2) only 38 where Isovue was mentioned and a superiority claim that could arguably be construed from the note; and (3) 1,251 notes from a single GEH sales representative (Chad Chaney) who entered substantially the same comment for numerous notes.

I find that focusing on the subset of sales call notes that explicitly mention Isovue would understate of the number of sales calls that improperly made Visipaque superiority claims over all LOCM. GEH’s claim that Visipaque is better than all LOCM or a LOCM, without identifying the one LOCM compared, is what makes its advertising campaign problematic; a sales call need not mention Isovue specifically.

In sum, Bracco’s position that any advertisement which references NEPHRIC is false is incorrect and thus results in an over-inclusive determination; conversely, GEH’s position that only those advertisements which compare or mention Isovue may be improper is under-inclusive. 5.

Evidence Concerning Materiality The evidence of materiality includes: • The repetition of certain unsupported claims by GEH’s sales and marketing teams. • The substance of the claims (e.g., CIN and other clinical data), which cannot be anecdotally observed with reliability (e.g., P260:413; 5 T 28-29). •The type of claims — i.e., drug safety, which GEH’s own observations (7 T 178) and market research showed were the most effective in converting sales (E.g., P100-102, 104-106, 196:573-580, 1400,1436,1716:739, 2038, 2112). • The limited evidence that it will take several years for Braceo to recover from GEH’s false claims once they are stopped (17T 117-118; 21 T 110-122).

These few examples, when considered in conjunction, demonstrate that GEH’s false advertising claims appear material to a consumer’s purchasing decision. Moreover, because I find that some of GEH’s claims are literally false, as stated infra p. 143-45, there is a presumption of materiality and deception. 6. Harm, Damages And Other Remedies a. Causation For Bracco’s Losses i. GEH’s Testimony and Business Records Numerous GEH witnesses conceded that Visipaque renal safety claims drove substantial sales increases which came, in significant part, at Bracco’s expense.

GEH’s President, Dan Peters, testified that GEH enjoyed a dramatic sales increase after the publication of NEPHRIC, primarily due to GEH’s renal safety message. (6 T 103; see also 7 T 94-95; P2461, 1892:925-6). He acknowledged that GEH’s renal message had a “large impact” on the “whole market” while GEH tried to “minimize [Nephric’s] negative impact on Omnipaque.” (6 T 59-60, 100). GEH’s Vice President of Sales, Don Quinn, confirmed that the “NEPHRIC data coupled with a very consistent targeted marketing campaign has propelled demand for Visipaque to new heights.” (8 T 124-125; P849:934).

He further admitted that GEH used NEPHRIC to convert competitive business, including Isovue accounts. Mr. Quinn agreed that GEH set out to increase Visipaque’s market share through an “aggressive sales and marketing effort” and that there “[absolutely” was a connection between that effort and these increases. In addition, GEH’s global brand manager, Mr. Paul Gehris, admitted that GEH saw “very good share growth since the NEPHRIC” that was “driven by awareness of the data and the perceived differentiation.” (13 T 77-80, 14-19; P1694:022).

However, it remains that out of the entire GEH ad campaign relating to Visipaque, only a small fraction of the disseminated messages were indeed false. Most were proper and were backed up by the underlying scientific studies that they reference. Therefore, a causal connection cannot be made by a sales trend alone; the accurate touting of favorable results of reliable scientific studies plays too much of a significant

part in this case to determine that the limited number of false ads disseminated are the cause of Bracco’s lost profits. GEH sales representatives also gave testimony relating to GEH’s renal superiority claims. GEH’s representative salesperson, Mr. Murray, testified during his deposition that in general, when talking with customers about high risk patients, he discusses that the NEPHRIC study shows that Visipaque has a better renal profile than traditional LOCM. (See 16 T 84:4-11). However, when a question relating to that statement was posed to Mr. Murray at trial, Mr.

Murray clarified his statement to mean that “when we were talking about NEPHRIC and the traditional LOCM, we were talking about [] Omnipaque.” Id. 14-17. In fact, Mr. Murray testified that as a sales representatives “he tr[ied] to talk about Omnipaque and Visipaque.” While it is difficult for the Court determine what was actually communicated to the customers, based on Mr. Murray’s testimony, some of this sales calls’ messages may be construed as misleading, especially when Mr. Murray did not qualify or specifically identity Omnipaque as being the traditional LOCM.

Nonetheless, the Court finds in its review of the sales call notes that the instances of sales reps making such misleading statements were limited. Importantly, the majority of GEH’s messages were in fact true and properly relied on reliable scientific studies to support them. GEH admitted that Visipaque’s premium price resulted from its “clinical differentiation” messages. Mr. Quinn testified that customers “absolutely” had to believe Visipaque provided patient benefits to pay the price premium.

The 2004 Marketing Plan states that “based upon its clinical differentiation ... a significant price premium has been placed on Visipaque when compared to low osmolar products.” Mr. Gehris admitted the clinical differentiation strategy drove Visipaque’s premium price. (13 T 14-19; P1436:616,622,635). However, this was in large part a result of the underlying studies and GEH’s promotion of their results.

Quotes from GEH business records relating to GEH’s claims of renal differentiation include, for example: • “The objective ... to increase market share ... will be accomplished strategically by clinically differentiating Isosmolar Visipaque from all other LOCM products....” (P849:932; 8 T 123-124). • “The Nephric success stories continue to come in with the majority of new dollars coming from competitive LOCM products.” (P1311) • “Sales performance reflects strong continued efforts in all markets to communicate NEPHRIC results and Visipaque clinical differentiation message ....

Sales reports continue to highlight customer acceptance of these messages and adoption of Visipaque use in patients at risk of CIN.” (P1157:744) • “2005 is projected to be the 3rd consecutive year of very aggressive growth____The NEPHRIC data, coupled with a very consistent and targeted marketing campaign ... has propelled demand for Visipaque to new heights.” Because the NEPHRIC study itself concluded that Visipaque may perform better than a LOOM, and that conclusion accurately reports the study’s findings, GEH’s internal documents which advocate differentiation of Visipaque from other LOCM did not lead to a false message so long as GEH actually disseminated an accurate portrayal of the NEPHRIC results and did not extrapolate them beyond the limited comparison of Visipaque and Omnipaque.

However, to the extent that GEH did not so limit its comparison and message, it would result in a false message. ii.Sales Trends In the LOCM market, three players (GEH, Braceo and Tyco) control 97% of the market, with Tyco’s share almost entirely due to the Premier GPO. (P849:881; 8 T 123 (Quinn), 18 T 114 (Malackowski), 21 T 91-92 (Medici)). The Court finds that, outside of the Premier GPO (which is not part of Bracco’s damages claim), the LOCM market effectively is a two-player market.

This finding is reinforced by the undisputed facts of record that Braceo and GEH were effectively the only two competitors for the Novation, Consorta and Kaiser contracts (as discussed below). Mr. Medici testified both parties’ market shares were stable but “changed dramatically” after the NEPHRIC

article was published and its subsequent marketing, with GEH’s sales increasing and Bracco’s decreasing. (21 T 93, 97, 103-104, 110-113). Mr. Peters agreed that initially Visipaque had grown only gradually but “grew very well after the NEPHRIC study, yes.” (6 T 44). iii. The Parties’ Surveys The Court is excluding both Bracco’s survey expert, Dr. Rappeport, as well as GEH’s survey expert, Dr. Ericksen. However, Mr.

Quinn, GEH’s Vice President of Sales, in an email to GEH officials, announced the results of an informal study of physicians and their feedback regarding the NEPHRIC article, including the “top 3 messages that excite physicians to action,” “Safety inpatient with creatine above 1.5,” “Less Nephropathy” and “Isosmolar Visipaque is 11 times less likely to cause renal failure.” In this case, each of these general statements may be part of a true advertising campaign, but only if they plainly describe the circumstances of the underlying studies, e.g. type of patients tested, and the actual products that were tested (and not in small footnoted material); GEH may not extrapolate these findings to CM which were not compared in these studies. iv.

Bracco’s Harm and Response Mr. Medici and Dr. Spinazzi testified that Braceo expended substantial resources, including spending millions of dollars, responding to the effects of GEH’s allegedly false claims — e.g., responding to purportedly deceived customers; responsive advertising; sponsorship of the Sharma, Solomon and Solomon/DuMouchel papers; and two head-to-head Visipaque versus Isovue studies (CARE and IMPACT). (E.g., 20 T 108-149; 21 T 99-110).

Braceo alleges that GEH’s false ads caused Braceo and Isovue to lose significant reputation and goodwill. (Id.) However, Bracco’s complaints about spending additional funds to sponsor studies verifying its product’s efficacy cannot all be laid at the feet of GEH. Braceo and GEH are the primary players in the field of CM and thus, fiercely compete against each other in the marketplace, obviously target each other, and look to tout their own products whenever possible.

Indeed, as shown during the course of the trial, by way of the sheer number of sponsored studies proffered by both parties over the years, in this business it appears to be commonplace, if not a necessary part of the industry, for companies to spend significant amounts of capital in support of scientific comparative studies to promote sales of their products. Moreover, the Court was surprised by the revelations that virtually every clinical trial, study, and resultant publication in this area was sponsored by GEH or Braceo. In some cases, the principal i

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