pan!-J f\ Thomas H. Bienert, Jr., State Bar No. 135311 tbienert@bmkattorneyS.com Ariana Seldman Hawbecker, State Bar No. 190506 ahawbecker@bmkattorneys.com BIENERT, MILLER KATZMAN, PLC 903 Calle Amanecer, Suite 350 San Clemente, California 92673 Tel: (949) ax (949)369-3701 Reuben A. Guttman (admitted pro hac vice) rguttman@gelaw.com Traci L. Buschner (admitted pro hac vice) tbuSchner@gelaw.com David T. FiScher(admitted pro hac vice) dfiScher@gelaw.com GRANT EISBNHOFER P.A. 1747 Ave., NW, Suite 875 Washington, DC 20006 Tel: (202) ax: (202) 386-9505 Jay W. Eisenhoffer (admitted pro hac vice) jeiSenhofer@gelaw.com GRANT EISBNHOFER P.A. 485 Lexington Avenue, 29th Floor New York, NY 10017 Tel: (646) ax: (646) 722-8501 Attomeys for Plaintiff-Relator Beverly Brown .aSe Document 72 Filed 02/05/14 Page 1 of 141 Page ID #:1273 OtEm<,UNITED STATES DISTRICT COURT CENTRAL DISTRICT OF CALIFORNIA -- WESTERN DIVISION UNITED STATES OF AMERICA, the States COLORADO, CONNECTICUT DELAWARE FLORIDA, GEORGIA, HAWAII, ILLINOIS, INDIANA, LOUISIANA, MARYLAND, MASSACHUSETTS, MICHIGAN, MINNESOTA MONTANA NEVADA NEW HAMPSHIRE NEW JERSEY NEW MEXICO, NEW YORK NORTH CAROLINA OKLAHOMA RHODE ISLAND TENNESSEE TEXAS, VIRGINIA WASHINGTON WISCONSIN, the DISTRICT OF COLUMBIA, and the CITY OF CHICAGO, Plaintiffs, Case No. 10-cv-03165 GHK (SSX) THIRD AMENDED COMPLAINT Case No. 10-cv-03165 GHK (SSX) THIRD AMENDED COMPLAINT DEMAND FOR JURY TRIAL Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 2 of 141 Page ID #:1274 1 2 Ex rel. BEVERLY BROWN, 3 4 Plaintiff-Relator, v. 5 CELGENE CORPORATION, 6 Defendant. 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Case No. 10-cv-03165 GHK (SSx) THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 3 of 141 Page ID #:1275 1 TABLE OF CONTENTS 2 Page 3 I. INTRODUCTION ............................................................................................... 1 4 II. JURISDICTION AND VENUE .......................................................................... 7 5 III. PARTIES .............................................................................................................. 8 6 IV. STATUTORY AND REGULATORY PROVISIONS APPLICABLE TO DEFENDANT CELGENE’S FALSE CLAIMS ACT VIOLATIONS ................ 9 7 8 A. Federal Government Health Programs ...................................................... 9 9 B. The False Claims Act .............................................................................. 12 10 C. FDA Regulations ..................................................................................... 12 11 D. Medicare and Medicaid Coverage Of Off-Label Prescriptions .............. 15 12 E. The Medicare Fraud & Abuse/Anti-Kickback Statute ............................ 18 13 F. Stark Law - The Medicare/Medicaid Self-Referral Statute .................... 19 14 G. The California Insurance Frauds Prevention Act .................................... 20 15 16 V. SPECIFIC ALLEGATIONS OF CELGENE’S FALSE CLAIMS .................... 21 A. Celgene’s Prescription Drugs Thalomid and Revlimid........................... 21 17 1. Thalomid’s FDA-Approved Uses and Restrictions ...................... 21 18 2. Revlimid’s FDA-Approved Uses and Restrictions ....................... 23 19 3. 20 Safety Issue: FDA Warnings Concerning Potentially Fatal Side Effects of Thalomid and Revlimid ................................................ 24 21 a. History of Thalomid ........................................................... 24 22 b. Thalomid’s and Revlimid’s Black Box Warnings Concerning Venous Thromboembolism ............................. 26 c. Thalomid’s and Revlimid’s Additional Safety Risks ......... 28 23 24 25 26 27 28 B. Celgene Engaged In a Wide Variety of Illegal Marketing Schemes To Promote Thalomid and Revlimid For Off-Label Use ............................. 29 1. Celgene Gave Its Staff Purposefully Misleading Titles ................ 29 2. Celgene Rewarded Its Sales Force For Their Off-Label Sales ..... 31 Case No. 10-cv-03165 GHK (SSx) i THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 4 of 141 Page ID #:1276 1 3. Celgene Was Aware Of The Serious Health Risks Caused By Thalomid And Revlimid But Trained Its Sales Force To Conceal The Facts ....................................................................................... 32 4. Celgene Repeatedly Trained Relator and Other Sales Personnel To Market Thalomid and Revlimid Off-Label And Then Managed Them To Ensure That They Were Marketing Off-Label36 2 3 4 5 6 7 a. Celgene Never Trained Its Sales Force To Market Thalomid On-Label ............................................................ 37 b. Celgene Trained Its Sales Force To Market Thalomid and Revlimid Off-Label at National Sales Meetings And By Bringing Relator and Other Sales Personnel To Corporate Headquarters ....................................................................... 38 c. Management Accompanied Relator and Other Sales Representatives on Sales Calls ........................................... 41 d. Celgene’s Misbranding Was Directed By Company Management ....................................................................... 43 8 9 10 11 12 13 14 15 16 5. Celgene Provided Its Sales Force With Marketing Materials Describing Off-Label Uses of Thalomid and Revlimid................ 44 6. Celgene Promoted Off-Label Uses of Thalomid and Revlimid Using Studies and Abstracts That Failed To Provided Scientific Support for the Off-Label Use ...................................................... 46 7. Celgene Trained Its Sales Personnel To “Probe” Physicians In Order to Induce Discussions of Off-Label Thalomid and Revlimid Uses ............................................................................... 52 8. To Provide Cover For The Company, Celgene Directed Its Sales Force to Secure Off-Label Medical Request Forms ..................... 54 9. Celgene Directed Its Sales Force To “Push The Dose” With Thalomid ....................................................................................... 56 17 18 19 20 21 22 23 24 25 26 27 28 Case No. 10-cv-03165 GHK (SSx) ii THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 5 of 141 Page ID #:1277 1 10. Celgene Provided Relator and Other Sales Personnel With “Training” Materials Describing Off-Label Uses, Most of Which Failed to Provide Scientific Support For the Off-Label Use ........ 57 11. Celgene Manipulated Continuing Medical Education Programs To Off-Label Market Thalomid And Revlimid ............................. 80 12. Relator And Other Sales Representatives Were Required To Conduct Training Sessions Concerning Thalomid’s Off-Label Uses ............................................................................................... 83 13. Celgene Provided Thalomid and Revlimid To Patients To Treat Off-Label Diseases ........................................................................ 83 2 3 4 5 6 7 8 9 10 11 C. Sales Representatives Encouraged Physicians to Switch Patients From Thalomid To Revlimid Regardless Of Whether The Patients Were Stable ....................................................................................................... 84 D. 15 Celgene Manipulated the FDA Mandated Patient Protection Programs to Market Its Products Off-Label ............................................................ 86 16 1. Celgene Created a Position, the Patient Support Coordinator, to Assist Patients in obtaining Government Funding for these Drugs ............................................................................................. 86 2. Celgene Manipulates RevAssist To Cause Medicare And Medicaid To Pay For Off-Label Revlimid Prescriptions .............. 88 12 13 14 17 18 19 20 21 E. Celgene Pays Kickbacks To Physicians To Prescribe Thalomid and Revlimid And To Encourage Other Physicians To Prescribe The Drugs ....................................................................................................... 92 F. Celgene Directly Targets Federal And State Healthcare Dollars ............ 97 22 23 24 25 1. Celgene Targeted Veterans Administrations And TRICARE ....... 98 26 2. 27 Celgene Targeted Private Payors, Including Insurers In California ...................................................................................... 99 28 REQUEST FOR TRIAL BY JURY ........................................................................... 122 Case No. 10-cv-03165 GHK (SSx) iii THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 6 of 141 Page ID #:1278 1 2 I. INTRODUCTION 1. With sometimes no more than a narrow window of opportunity to make 3 critical decisions about medical treatment, doctors and their patients must have honest 4 information about treatment options including appropriate drug regimens. 5 ravaged by cancer, and often on the edge of life, have no choice but to trust that their 6 healthcare providers and the pharmaceutical manufacturers are providing information 7 based on solid evidence, and that independent scientists at the Food and Drug 8 Administration (“FDA”) have reviewed their drugs for safety and efficacy. Patients 9 2. 10 United States. 11 Unfortunately, most of these potent treatments have toxic side effects and can be fatal 12 themselves. Therefore, Congress carefully balanced the need to speed treatments to 13 desperately ill patients with the need for reliable evidence that the benefits of new 14 treatments outweighed their risks. Congress created the FDA to independently evaluate 15 the safety and efficacy of each new drug, for each intended use, before a manufacturer 16 could put it on the market in the United States. In 1992, it amended the Food Drug and 17 Cosmetic Act (“FDCA”) to create an accelerated approval process for drugs for which 18 there was an urgent need. The FDA requires pharmaceutical manufacturers to develop 19 adequate evidence to allow doctors and their patients to make informed decisions about 20 the best treatment. 21 3. Cancer is a dread disease, still the second leading cause of death in the In the last 30 years, new treatments have come on the market. This case is about a large drug manufacturer, Celgene Corporation 22 (“Celgene” or the “Company”), that deliberately chose to ignore this process and preyed 23 on a vulnerable patient population. By marketing drugs to cancer patients and their 24 doctors for unapproved purposes and paying kickbacks to physicians, Celgene 25 compromised physicians’ professional judgment so that they would make decisions not 26 based solely on scientific evidence. 27 Thalidomide, and later Revlimid, a related compound – on the market and sold them for 28 all types of cancer without any of the research the FDA requires or the oversight it Case No. 10-cv-03165 GHK (SSx) Celgene put an old, highly toxic drug – 1 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 7 of 141 Page ID #:1279 1 provides. Celgene persevered with its unlawful marketing conduct even after receiving 2 warning letters from the FDA in 1998 and 2000. 3 endangered 4 thromboembolism and death associated with Thalomid use in cancer patients. When 5 Celgene ultimately secured an indication for a treatment of multiple myeloma (“MM”) 6 with Thalomid, that approval was conditioned on the package insert containing a black 7 box warning – the most serious warnings given out by the FDA – alerting doctors and 8 patients of the risks of venous thromboembolism. 9 4. patients because it knowingly Celgene’s unlawful marketing concealed the risks of venous While this case is ultimately about the wrongful expenditure of government 10 and private payor monies for prescriptions flowing from unlawful marketing schemes, 11 Celgene’s conduct compromised or potentially compromised medical care for countless 12 cancer patients. Celgene racked up hundreds of millions of dollars a year in sales for 13 purposes not approved by the FDA by pushing drugs to treat cancers even though there 14 were well-known, evidence-based treatments that worked as well or better than 15 Thalomid and its cousin, Revlimid. Celgene profited by persuading – and sometimes 16 paying – doctors to substitute its untried remedies for treatments proven to be safe and 17 effective in desperately ill patients. Celgene, a multi-billion dollar company, was built 18 on profits derived from unlawful marketing. 19 5. Without any of the research or oversight the FDA requires, Celgene placed 20 thalidomide, which caused horrific birth defects in the 1960’s, back on the market for all 21 kinds of cancer. The story begins in 1998, when Celgene secured from the FDA an 22 indication that it never intended to use for a skin disease, erythema nodosum leprosum 23 (“ENL”), associated with leprosy. There was no profit in treating a disease that affects 24 less than a few hundred people a year in the United States. So Celgene never developed 25 substantive marketing materials about ENL or trained its sales representatives to sell 26 Thalomid to physicians who treat leprosy. Instead of marketing Thalomid for its limited 27 ENL indication, Celgene violated explicit FDA regulations prohibiting misbranding 28 including off-label marketing: Celgene flooded the country with sales representatives Case No. 10-cv-03165 GHK (SSx) 2 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 8 of 141 Page ID #:1280 1 under heavy pressure to sell Thalomid, and later Revlimid, to oncologists for whatever 2 cancer they treated, blood cancers as well as solid tumors, on the basis of minimal 3 evidence. As early as 1999, in its Annual Report to shareholders, Celgene announced 4 that more than 90% of Thalomid prescriptions were for oncology, a purpose not 5 approved by the FDA. 6 6. From the beginning, the FDA warned Celgene about these illegal off-label 7 marketing efforts. Celgene received its FDA approval for ENL on July 16, 1998; 15 8 days later the FDA contacted Celgene “to discuss concerns about promotional materials 9 containing uses of thalidomide other than those” approved by the FDA. Four months 10 later, it sent Celgene a warning letter regarding its marketing, including a press release 11 entitled “Celgene Announces Plans to Pursue Multiple Myeloma Indication for 12 THALOMID.” The FDA criticized Celgene for failing to present any information 13 concerning “the significant, potentially fatal, risks associated with the use of thalidomide 14 ....” On December 22, 1998, FDA staff met with Celgene executives and expressed 15 “strong concern regarding Celgene’s promotion of unapproved use of thalidomide, and 16 its failure to fully state risks.” On April 21, 2000, the FDA sent Celgene another 17 warning letter because “Celgene [had] engaged in promotional activities that state or 18 suggest that Thalomid is safe and effective for use in treating multiple myeloma.” The 19 FDA was particularly concerned about Celgene’s conduct relating to Thalomid because 20 “[p]erhaps more than for any other available drug, the need to provide and distribute 21 thalidomide responsibly is essential to the public health.” The FDA stated that: 24 Celgene is demonstrating a continuing pattern and practice of violative behavior that evince its failure to comply with the conditions under which Thalomid was approved. Previous discussions with Celgene have not resulted in Celgene’s compliance with the Act. 25 7. 22 23 At the time the FDA issued this warning letter, investment analysts 26 estimated that Celgene’s sales were almost all off-label. For example, in 2000, U.S. 27 Bancorp Piper Jaffery analyst Peter Ginsburg estimated that 90% of Thalomid’s 1999 28 sales were for cancer. Celgene’s sale of Thalomid continued to be overwhelmingly for Case No. 10-cv-03165 GHK (SSx) 3 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 9 of 141 Page ID #:1281 1 cancer. Bob Hugin, the then-CF of Celgene Corp., stated at the Lehman Brothers Global 2 Health Care Conference on or about Mar. 31, 2005 that about 92% of Thalomid 3 prescriptions were for cancer. Mr. Hugin boasted that Thalomid was the “financial 4 engine” powering Celgene’s growth, delivering the company’s first full-year positive 5 earnings in 2003. 6 8. Celgene’s initial marketing efforts for Thalomid were tantamount to 7 ongoing human experimentation. Because Celgene marketed the drug off-label, patients 8 and their medical advisors were denied the appropriate warnings provided in a package 9 insert when a product is used on-label. For example, by 2003, if not earlier, Celgene 10 was aware that there was a serious risk of increased venous thromboembolism in 11 multiple myeloma (“MM”) patients taking Thalomid. Rather than disclose this deadly 12 risk to doctors and their patients, Celgene trained its sales representatives to either 13 conceal or downplay the risk. 14 9. In late 2005, Celgene secured an FDA indication for a derivative of 15 Thalomid which it named Revlimid. The FDA approved a single, limited indication for 16 Revlimid for a relatively uncommon subtype of the blood disorder, myelodysplastic 17 syndrome (“MDS”) (transfusion-dependent anemia due to low or intermediate risk MDS 18 when associated with a deletion 5q cytogenic abnormality with or without additional 19 cytogenic abnormalities), an early stage of cancer. 20 proceeded to market Revlimid for a variety of cancers for which it had not obtained 21 indications. 22 10. As with Thalomid, Celgene Revlimid proved to be a miracle drug for Celgene’s revenue stream, 23 because it was ten times more costly than Thalomid. Celgene began an aggressive 24 campaign to switch Thalomid patients to Revlimid. In practical terms, this meant that a 25 patient’s – or his/her insurer’s – monthly cost would rise from $2,000 per month to 26 $10,000 per month. (To reduce the financial disincentive to switch, Celgene gradually 27 raised the price of Thalomid to $5,000 per month.) 28 Case No. 10-cv-03165 GHK (SSx) 4 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 10 of 141 Page ID #:1282 1 11. After years of flouting the Food Drug and Cosmetics Act’s proscriptions 2 against off-label marketing, in May 2006, Celgene finally obtained a new indication for 3 Thalomid for the very limited purpose of treating newly diagnosed MM patients who 4 had not undergone any other prior treatment. The indication also required that Thalomid 5 be used in combination with another drug, dexamethasone. The approval required 6 placement of a black box warning of increased risk of venous thromboembolism in MM 7 patients. With this black box warning on the face of the Thalomid label, the Company 8 could no longer conceal the increased and deadly risk of venous thromboembolism to, at 9 least, MM patients. 10 12. One month later, in June 2006, Celgene secured another indication for 11 Revlimid allowing it to market for a second narrow indication for MM taken in 12 combination with dexamethasone, for patients who had received at least one prior 13 therapy. Thus, in contrast to Thalomid, Revlimid was not approved for newly diagnosed 14 MM patients. As of 2012, Celgene’s drugs Thalomid and Revlimid had not received 15 any indications for cancers other than MM and MDS. Yet, through continued off-label 16 marketing, kickbacks and concealment of risks, Celgene was able to secure a revenue 17 stream in the billions of dollars. This revenue stream exponentially exceeded the on- 18 label market for Celgene’s drugs. Celgene generated sales exceeding a hundred million 19 dollars a year for Thalomid from 1998 through 2005, culminating in sales of 20 approximately $389 million in 2005 alone. Revlimid sales in 2008 and 2009 totaled 21 more than $1.7 billion and have continued to increase with more than a billion dollars in 22 sales every year since then. 23 13. Because Thalomid and Revlimid cause severe birth defects, the FDA 24 mandated that the Company implement a restricted distribution system requiring 25 physicians to follow specific procedures before prescribing these drugs. In its effort to 26 market Thalomid and Revlimid, the Company transformed a system required by the 27 FDA to prevent birth defects into a system for reaching more doctors. Under the guise 28 of assisting physicians with the FDA restrictions, Celgene dispatched more than 100 Case No. 10-cv-03165 GHK (SSx) 5 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 11 of 141 Page ID #:1283 1 sales representatives across the country with purposefully misleading titles, including 2 Immunology Specialist and Hematology Oncology Consultant, in order to gain access to 3 doctors’ offices and carry out Celgene’s unlawful marketing objectives. 4 14. Despite being charged with implementing measures to prevent birth defects, 5 Celgene’s sales representatives were, and continue to be paid, bonuses based on off-label 6 and on-label drug sales. 7 8 9 15. During relevant time periods, Celgene marketed Thalomid for at least 19 off-label uses and Revlimid for at least nine off-label uses. 16. During relevant time periods, there were other FDA approved treatments 10 available for all of these diseases. Celgene’s off-label marketing of Thalomid and 11 Revlimid exposed patients to magnified risks of potentially fatal blood clots, potentially 12 fatal skin conditions, severe nerve damage, decreased white blood cell counts, and other 13 side effects. 14 17. Celgene caused false claims to be submitted in violation of the law for 15 payment by federal and state agencies or programs, and by private insurers including 16 those operating in the state of California by: 17  systematically engaging in illegal off-label marketing of its drugs, Thalomid (generic name “thalidomide”) and Revlimid (generic name “lenalidomide”);  furthering the unlawful off-label marketing of Thalomid and Revlimid through violations of continuing medical education (“CME”) rules and regulations by directing and controlling the content of physician speaker programs that purported to be unbiased;  unlawfully promoting Thalomid and Revlimid in violation of the AntiKickback Statute, 42 U.S.C. § 1320a-7b(b), and the Stark Law, 42 U.S.C. § 1395nn and 42 C.F.R. § 411.350 et seq., by providing cash and other incentives to induce doctors to promote and prescribe these drugs, including for off-label uses; and  unlawfully tampering with Revlimid prescriptions to deceive Medicare, Medicaid, and other government-funded programs into believing that offlabel prescriptions were for on-label indications. 18 19 20 21 22 23 24 25 26 27 28 Case No. 10-cv-03165 GHK (SSx) 6 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 12 of 141 Page ID #:1284 1 18. Celgene’s illegal marketing of Thalomid and Revlimid caused federal, state 2 and local government health care programs, as well as private insurers including those 3 operating in the state of California, to pay for millions of prescriptions that never would 4 have been submitted for reimbursement but for Celgene’s activities. In addition to the 5 federal healthcare dollars expended through Medicare and Medicaid, state governments 6 spend money through Medicaid, as well as through their state workers’ insurance plans. 7 The City of Chicago expends municipal dollars to insure its own workers. Had federal, 8 state, and city programs, including Medicare and Medicaid, as well as private insurers 9 including those operating in the state of California, known that such prescriptions were 10 induced by illicit incentives or illegal off-label marketing to physicians, they would not 11 have reimbursed claims for Thalomid or Revlimid. 12 19. Relator discovered Celgene’s wrongful conduct while she was employed by 13 Celgene. She conducted her own investigations in furtherance of this action and 14 disclosed her findings to the United States Government and the states prior to filing this 15 action. 16 20. On behalf of the United States of America and on behalf of California, 17 Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Illinois, Iowa, Indiana, 18 Louisiana, Maryland, Massachusetts, Michigan, Montana, Nevada, New Hampshire, 19 New Jersey, New Mexico, New York, North Carolina, Oklahoma, Rhode Island, 20 Tennessee, Texas, Virginia, Washington, Wisconsin, the District of Columbia, and the 21 City of Chicago, pursuant to the qui tam provisions of the federal False Claims Act , 31 22 U.S.C. § 3729 et seq., and similar state law and municipal provisions, and the California 23 Insurance Frauds Prevention Act, Cal. Ins. Code § 1871.7, Plaintiff 24 Beverly Brown files this qui tam Complaint against Defendant Celgene Corporation. 25 II. 26 or “Relator” JURISDICTION AND VENUE 21. Relator brings this action on behalf of herself and on behalf of the United 27 States for violations of the False Claims Act, 31 U.S.C. §§ 3729-3733, and on behalf of 28 California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Illinois, Iowa, Case No. 10-cv-03165 GHK (SSx) 7 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 13 of 141 Page ID #:1285 1 Indiana, Louisiana, Maryland, Massachusetts, Michigan, Montana, Nevada, New 2 Hampshire, New Jersey, New Mexico, New York, North Carolina, Oklahoma, Rhode 3 Island, Tennessee, Texas, Virginia, Washington, Wisconsin, the District of Columbia, 4 and the City of Chicago for violations of their respective state false claims acts. Relator 5 also brings this action pursuant to Cal. Ins. Code § 1871.7, the California Insurance 6 Frauds Prevention Act. 7 22. This Court has federal subject matter jurisdiction over this action pursuant 8 to 28 U.S.C. § 1331 and 31 U.S.C. § 3732 and supplemental jurisdiction over the counts 9 relating to the State False Claims Acts pursuant to 28 U.S.C. § 1367. 10 23. This Court has personal jurisdiction over the Defendant pursuant to 31 11 U.S.C. § 3732(a) because the Defendant can be found in and transacts business in this 12 District. In addition, the acts prohibited by 31 U.S.C. § 3729 occurred in this District. 13 24. Venue is proper in this District pursuant to 31 U.S.C. § 3732(a) because 14 Defendant transacts business in this District and numerous acts proscribed by 31 U.S.C. 15 § 3729 occurred in this District. 16 25. There has been no public disclosure of the allegations herein. To the extent 17 that there has been a public disclosure unknown to the Relator, she is the “original 18 source” under 31 U.S.C. § 3730(e)(4) and similar state laws. Relator has direct and 19 independent knowledge of the information on which the allegations are based and has 20 voluntarily provided the information to the Government before filing this qui tam action 21 based on that information. See 31 U.S.C. § 3730(e)(4). 22 III. 23 PARTIES 26. Relator Beverly Brown was employed by Celgene from 2001 to 2011, 24 working in Los Angeles, California and surrounding areas. Her job titles included 25 S.T.E.P.S. (System for Thalidomide Education and Prescribing Safety) Field 26 Coordinator, Immunology Specialist, and Hematology Oncology Consultant. Although 27 Celgene bestowed upon her these science-related job titles, Relator was in truth a 28 pharmaceutical sales representative who received a base salary and bonuses based on the Case No. 10-cv-03165 GHK (SSx) 8 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 14 of 141 Page ID #:1286 1 volume of both on-label and off-label sales of Thalomid and Revlimid in her sales 2 district. Relator was a top performer, winning commendations from Celgene for her 3 sales performance. 4 27. Defendant Celgene is a Delaware corporation, with its headquarters and 5 principal place of business in Summit, New Jersey. Celgene holds itself out as a global 6 biopharmaceutical company engaged in the business of discovery, development, 7 manufacturing, marketing, and sales of prescription drugs and other products for the 8 prevention, diagnosis, and treatment of diseases. Yet until at least 2005, almost all of 9 Celgene’s revenue was attributable to the use of its drugs for purposes not approved by 10 the FDA. 11 Thalomid generating $2.7 billion and Revlimid generating $4 billion. According to 12 Company estimates (see Celgene Q4 2008 Earnings Call (Jan. 29, 2009)), as well as 13 industry analysis (see Credit Suisse Analyst Report (Apr. 1, 2009)), Medicare and 14 Medicaid paid for the majority of Thalomid and Revlimid prescriptions. 15 IV. Thalomid and Revlimid generated $6.7 billion in sales revenues, with 16 STATUTORY AND REGULATORY PROVISIONS APPLICABLE TO DEFENDANT CELGENE’S FALSE CLAIMS ACT VIOLATIONS 17 A. Federal Government Health Programs 18 28. The federal and state governments are among the principal purchasers of 19 Celgene’s pharmaceutical products, primarily but not exclusively through their Medicaid 20 and Medicare programs. Private insurers, including those operating in California, also 21 pay for Celgene’s pharmaceutical products. 22 29. Medicare is a federal government health program primarily benefiting the 23 elderly and disabled that Congress created in 1965 when it adopted Title XVIII of the 24 Social Security Act. 25 Medicaid Services (“CMS”). 26 30. Medicare is administered by the Centers for Medicare and There are four parts to Medicare: Medicare Part A (hospital insurance); 27 Medicare Part B (medical insurance); Medicare Part C (Medicare Advantage, formerly 28 known as Medicare + Choice); and Medicare Part D (prescription drug coverage that Case No. 10-cv-03165 GHK (SSx) 9 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 15 of 141 Page ID #:1287 1 was enacted as part of the Medicare Prescription Drug, Improvement, and 2 Modernization Act of 2003 (“MMA”) and went into effect on January 1, 2006). 3 31. Medicare Part A generally pays for inpatient services for eligible 4 beneficiaries in hospitals, hospices and skilled nursing facilities, as well as some home 5 healthcare services. 42 U.S.C. §§ 1395e - 42 U.S.C. §§ 1395i-5. Prescription drugs are 6 covered under Medicare Part A only if they are administered on an inpatient basis in a 7 hospital or similar setting. 8 32. Medicare Part B covers some healthcare services and products not covered 9 by Medicare Part A, generally on an outpatient basis. Doctor’s visits and other services 10 are covered by Part B. Medicare Part B also pays for some types of prescription drugs 11 that are not administered in a hospital setting. 42 U.S.C. § 1395k(a); 42 U.S.C. § 12 1395x(s)(2); 42 C.F.R. § 405.517. These typically include drugs administered by a 13 physician or other provider in an outpatient setting, including some anticancer drugs. 42 14 U.S.C. § 1395k(a); 42 U.S.C. § 1395x(s)(2); 42 C.F.R. § 405.517. 15 33. Medicare Part C, in effect, combines both Part A and Part B. Part C differs, 16 however, because it is supplied through private insurance companies. 17 beneficiaries have the option to receive their Medicare benefits through private health 18 insurance plans, instead of through the original Medicare plan (Parts A and B). 19 Originally, these programs were known as “Medicare+Choice” or “Part C” plans. 20 Following the passage of the MMA – which created Part D – “Medicare+Choice” 21 became known as “Medicare Advantage” (“MA”) plans. 22 34. Medicare On January 1, 2006, Part D of the Medicare program began subsidizing 23 optional drug coverage for all beneficiaries. This drug benefit covers drugs that are 24 considered “covered outpatient drugs” under 42 U.S.C. § 1396r-8(k). 25 35. Congress created Medicaid at the same time it created Medicare in 1965 26 when Title XIX was added to the Social Security Act. Medicaid is a public assistance 27 program that provides payment of medical expenses for primarily low-income patients. 28 Funding for Medicaid is shared between the federal government and state governments. Case No. 10-cv-03165 GHK (SSx) 10 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 16 of 141 Page ID #:1288 1 The federal government also separately matches certain state expenses incurred in 2 administering the Medicaid program. While specific Medicaid coverage guidelines vary 3 from state to state, Medicaid’s coverage is generally modeled after Medicare’s coverage, 4 except that Medicaid usually provides more expansive coverage than does Medicare. 5 36. Medicaid, since its beginning, generally has had broad coverage for 6 prescription drugs, including self-administered drugs. Nearly every state has opted to 7 include basic prescription drug coverage in its Medicaid plan. 8 37. Medicaid pays for services pursuant to plans developed by the states and 9 approved by the U.S. Department of Health and Human Services (“HHS”) through 10 CMS. 42 U.S.C. §§ 1396a(a)-(b). After states pay doctors, hospitals, pharmacies, and 11 other providers and suppliers of medical items and services according to rates the states 12 establish, the federal government then pays each state a statutorily-established share of 13 “the total amount expended ... as medical assistance under the State plan....” See 42 14 U.S.C. §§ 1396b(a)(1), 1396b(a)(1), and 1903(a)(1). This federal-to-state payment is 15 known as federal financial participation (“FFP”). 16 38. TRICARE is the healthcare system of the United States military, designed 17 to maintain the health of active duty service personnel, provide healthcare during 18 military operations, and offer health care to non-active duty beneficiaries, including 19 dependents of active duty personnel and certain military retirees and their dependents. 20 The program operates through various military-operated hospitals and clinics worldwide 21 and is supplemented through contracts with civilian healthcare providers. Five managed 22 care support contractors create networks of civilian healthcare providers. 23 39. Whereas TRICARE treats active duty military and their dependents, the 24 Veterans Administration (“VA”) provides healthcare and other benefits to military 25 veterans through its nationwide network of hospitals and clinics. 26 40. The Federal Employees Health Benefits Program (“FEHBP”) provides 27 health insurance coverage for more than 8 million federal employees, retirees, and their 28 dependents. FEHBP is a collection of individual healthcare plans such as the Blue Cross Case No. 10-cv-03165 GHK (SSx) 11 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 17 of 141 Page ID #:1289 1 and Blue Shield Association. FEHBP plans are managed by the Office of Personnel 2 Management. 3 41. While each government-funded healthcare program establishes its own 4 reimbursement criteria, none knowingly pays for medications that are not prescribed for 5 a medically accepted indication or that are prescribed as a result of false or misleading 6 information disseminated by pharmaceutical manufacturers to either payors or 7 healthcare providers. In addition, none of the government-funded healthcare programs 8 willingly pay for drugs that were prescribed as the result of the pharmaceutical 9 manufacturer’s unlawful inducements or unlawful marketing activities. 10 B. The False Claims Act 11 42. The Federal False Claims Act provides that any person who knowingly 12 presents or causes another to present a false or fraudulent claim for payment or approval 13 is liable for a civil penalty of up to $11,000 for each such claim, plus three times the 14 amount of the damages sustained by the government. 31 U.S.C. §§ 3729(a)(1)(A), (B). 15 Twenty-nine states, the District of Columbia, and the City of Chicago have enacted 16 analogous false claims act statutes that apply to Medicaid fraud (the “State False Claims 17 Acts”). 18 C. FDA Regulations 19 43. The FDA regulates drugs based on the “intended uses” for such products. 20 Before marketing and selling a prescription drug, a manufacturer must demonstrate to 21 the FDA that the product is safe and effective for each intended use. 21 U.S.C. § 331(d); 22 21 U.S.C. §§ 355(a), 360b(a). 23 44. The FDA reviews pharmaceutical manufacturers’ applications for new 24 drugs to determine whether the drugs are safe and effective for each intended use. See 25 21 U.S.C. § 355. 26 45. Once a drug is approved for a particular use, doctors may legally prescribe 27 the drug for any “non-indicated” or off-label purpose. Doctors may independently 28 request information from drug manufacturers about such off-label uses. But with very Case No. 10-cv-03165 GHK (SSx) 12 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 18 of 141 Page ID #:1290 1 few exceptions, the FDA prohibits drug manufacturers from marketing or promoting 2 drugs for uses, i.e., indications, not explicitly approved by the FDA. As described 3 above, “off-label marketing” refers to the marketing of an FDA-approved drug for uses 4 that have not undergone FDA scrutiny and approval. 5 46. Under the statute, qualified medical professionals may provide purely 6 scientific medical information for uses other than those approved by the FDA; all other 7 presentations, promotions and marketing to physicians for uses other than those 8 approved by the FDA are considered off-label marketing or “misbranding” proscribed 9 by the Food, Drug and Cosmetics Act (“FDCA”). See 21 U.S.C. §§ 331(a)-(b), 352(a), 10 (f). This includes any attempts by a pharmaceutical sales representative to initiate 11 discussions with, or solicit questions from, physicians concerning off-label use. 12 47. Strong policy reasons exist for strict regulation of off-label marketing. Off- 13 label promotion bypasses the FDA’s strict review and approval process. It also removes 14 the incentive to obtain definitive clinical study data showing the efficacy and safety of a 15 product and, accordingly, the medical necessity for its use. 16 48. Pursuant to the FDCA, 21 U.S.C. § 301, et seq., the FDA strictly regulates 17 the content of direct-to-physician product promotion and drug labeling information used 18 by pharmaceutical companies to market and sell FDA-approved prescription drugs. 19 49. FDA interprets “labeling” in its regulations broadly to include items that are 20 “1) descriptive of a drug: 2) supplied by the manufacturer or its agents; and 3) intended 21 for use by medical personnel.” 21 C.F.R. § 202.1. The FDCA defines both misleading 22 statements and the omission of material facts in a label or product labeling as 23 “misbranding.” 21 U.S.C. § 321(n). Labeling includes brochures, booklets, detailing 24 pieces, literature, medical reprints, sound recordings, exhibits and audio visual material. 25 21 C.F.R. § 202.1 (l)(2). 26 50. The FDA regulations deem “advertising” to include any media-based 27 activities that appear in magazines, newspapers, professional journals and on television, 28 radio, and telephone communications systems. See 21 C.F.R. § 202.1(l)(1). Courts have Case No. 10-cv-03165 GHK (SSx) 13 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 19 of 141 Page ID #:1291 1 consistently held that oral statements made by a company’s sales representative relating 2 to a pharmaceutical product constitute commercial advertising or promotion. See Abbott 3 Labs. v. Mead Johnson & Co., 971 F.2d 6, 10 (7th Cir. 1992) (interpreting the Lanham 4 Act). 5 51. Pharmaceutical promotional and marketing materials and presentations 6 lacking in fair balance or that are otherwise false or misleading “misbrand” a drug in 7 violation of the FDCA, 21 U.S.C. §§ 301, 321, 331, 352, 360b, 371; 21 C.F.R. §§ 8 202.1(e)(6), (e)(7); 21 C.F.R. § 1.21. 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 52. Such violations exist where promotional and marketing materials and presentations for an FDA approved drug:  Minimize, understate, or misrepresent the risks, contra-indications, and complications associated with that drug;  Overstate or misrepresent the risks, contra-indications, and complications associated with any competing drugs;  Reference “off-label” uses of the drug — i.e., those uses that have not been approved by the FDA — or expressly or implicitly promote uses and/or dosing regimens for which the drug is not indicated;  Fail to reveal facts material in light of its representations or material with respect to consequences that may result from the use of the drug as recommended or suggested in the advertisement;  Contain representations or suggestions, not approved or permitted in the labeling, that is not demonstrated by substantial evidence or substantial clinical experience;  Present information from a study in a way that implies that the study represents larger or more general experience with the drug than it actually does;  Use a quote or paraphrase out of context to convey a false or misleading idea; or  Are otherwise false, misleading or lacking in fair balance in the presentation of information about the drug being marketed or about any competing drug. Case No. 10-cv-03165 GHK (SSx) 14 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 20 of 141 Page ID #:1292 1 2 See 21 C.F.R. §§ 202.1 (e)(4)(5)(6), (7). 53. Oral statements and written materials presented at industry-supported 3 activities, including lectures and teleconferences, provide evidence of a product’s 4 intended use. If these statements or materials promote a use inconsistent with the 5 product’s FDA-approved labeling, it is misbranded as it fails to provide adequate 6 directions for all intended uses. 7 D. Medicare and Medicaid Coverage Of Off-Label Prescriptions 8 54. By statute, Medicare and Medicaid can only reimburse claims for drugs if 9 the drug is dispensed for a “medically accepted indication.” See e.g., 42 U.S.C. § 1369r- 10 8(k). The law further provides a drug is dispensed for a “medically accepted indication” 11 if it is for a use that the FDA has approved. See, e.g., id. Thus, normally, Medicare and 12 Medicaid can only pay for pharmaceutical prescriptions if the doctor has prescribed the 13 drug for a use that the FDA approved. This makes sense as the FDA comprehensively 14 reviews pharmaceutical manufacturers’ detailed applications for new drugs to determine 15 whether the drugs are safe and effective for each intended use. See 21 U.S.C. § 355. 16 Congress requires Medicare and Medicaid to only pay for prescription drugs that are 17 safe and effective for their prescribed use. 18 55. There is an exception to Medicare and Medicaid’s FDA approval 19 requirement, however. The law also considers it a “medically accepted indication” - and 20 thus permits Medicare and Medicaid to reimburse - if the prescribed use is “supported by 21 citation” in one or more of several specified drug compendia. 22 1395x(t)(2)(B) and 42 U.S.C. § 1395w-102(2) (2007) (Medicare); 42 U.S.C. § 1396r- 23 8(k)(6) and 42 U.S.C. § 1396r-8(g)(1)(B)(l) (Medicaid). 24 56. 42 U.S.C. § The drug compendia are privately owned, written and published indices of 25 various pharmaceuticals products. For each product, a compendia includes information 26 about the product’s pharmacologic and pharmacokinetic properties (such as adverse 27 effects, and drug interactions) and the FDA-approved indications for that drug. The 28 Case No. 10-cv-03165 GHK (SSx) 15 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 21 of 141 Page ID #:1293 1 compendia also, however, includes information about studies of the product in diseases 2 not approved by the FDA and not listed on the label (i.e., “off-label” uses). 3 57. Under Medicare Part B, until 2008, the statute listed only three compendia 4 that CMS could consider: American Medical Association Drug Evaluations (AMA-DE), 5 United States Pharmacopoeia Drug Information for the Health Professional (USP-DI), 6 and American Hospital Formulary Service Drug Information (AHFS), 42 U.S.C. § 7 1395x. In 1994, the AMA and the U.S Pharmacopeial Convention agreed to combine 8 the AMA-DE and the USP-DI into a single reference; they agreed to use the USP-DI 9 name. In 1998, the USP-DI was sold to Thomson Healthcare, whose Micromedex 10 subsidiary published DrugDex. 11 Pharmacopeial Convention retained oversight of the USP-DI content until 2004 (when 12 control transferred to Thomson) and Micromedex was responsible for product 13 development, marketing and distribution. Publication of USP-DI ended in 2007. 14 15 16 58. Under the agreement with Thomson, the U.S When Part D came into effect in 2006, the statute allowed CMS to rely upon AHFS, USP-DI and DrugDex. 42 C.F.R. § 423.100. 59. Because two of the three original Part B statutory compendia had ceased 17 publication, following its rule-making process, in 2008 CMS added National 18 Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN), and 19 Clinical Pharmacology to the list of compendia (effective, June 5, and July 2, 2008 20 respectively) for both Part B and Part D and DrugDex for Part B (effective June 10, 21 2008). 22 60. The compendia portion of the Medicaid statute, by contrast, has been stable 23 for the relevant time period. It originally limited the approved compendia to AHFS and 24 the USP-DI. 42 U.S.C. § 1396r-8(g)(1)(B)(i). In 1997, Congress added DrugDex to the 25 approved list of compendia that Medicaid programs could consider. Balanced Budget 26 Agreement of 1997, Pub. L. 105-33 (amending 42 U.S.C. § 1396r-8(g)(1)(B)(i)). 27 28 Case No. 10-cv-03165 GHK (SSx) 16 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 22 of 141 Page ID #:1294 1 61. Coverage of off-label drug use by TRICARE, the VA and other federal and 2 state healthcare programs is similar to Medicare and Medicaid coverage. See, e.g., 3 TRICARE Policy Manual 6010.54-M, Chapter 8, Section 9.1. 4 62. From 1998 to the present day, Celgene marketed Thalomid for numerous 5 uses not approved by the FDA including bladder cancer, breast cancer, brain cancer, 6 cervical cancer, colorectal cancer, esophageal cancer, kaposi sarcoma, leukemia 7 (including, but not limited to, chronic lymphocytic leukemia (“CLL”)), lung cancer, 8 lymphoma, melanoma, prostate cancer, pancreatic cancer, renal (i.e., kidney) cancer, 9 thyroid cancer, new onset multiple myeloma (prior to the FDA’s May 26, 2006 approval 10 of Thalomid to treat one stage of this disease), multiple myeloma not in combination 11 with the drug dexamethasone, ovarian cancer, and uterine cancer. 12 63. During the relevant time period, the compendia did not provide adequate 13 support for using Thalomid to treat any of these diseases other than as approved by 14 FDA. During relevant time periods, Celgene illegally “off-label” marketed Revlimid for 15 brain cancer, leukemia (including, but not limited to, CLL), lymphoma, myelofibrosis, 16 myelodysplastic syndromes (all types), new onset multiple myeloma (prior to the FDA’s 17 approval of Revlimid to treat an indication for this disease), multiple myeloma not in 18 combination with the drug dexamethasone, prostate cancer, and stem-cell transplant 19 maintenance therapy. As with Thalomid, the compendia do not provide support for 20 using Revlimid to treat any of these medical conditions. 21 64. Accordingly, Medicare, Medicaid or other government healthcare programs 22 should not pay for Thalomid and Revlimid prescriptions to treat these conditions 23 because 24 1395x(t)(2)(B)(ii)(I). 25 65. the indications were not “medically accepted.” 42 U.S.C. § Notwithstanding the lack of support in the drug compendia, Celgene 26 attempted to influence the drug compendia. For example, Celgene paid 16 of the doctors 27 who advised the NCCN compendium on multiple myeloma. Three of these sixteen – Dr. 28 Case No. 10-cv-03165 GHK (SSx) 17 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 23 of 141 Page ID #:1295 1 Kenneth Anderson, Dr. Seema Singhal and Dr. Steven Treon – were also considered 2 “core faculty” for the Speaker Corps series described herein. 3 E. The Medicare Fraud & Abuse/Anti-Kickback Statute 4 66. The Medicare Anti-Kickback Statute, 42 U.S.C. § 1320a-7b(b), which also 5 applies to the state Medicaid programs, provides penalties for individuals or entities that 6 knowingly and willfully offer, pay, solicit, or receive remuneration to induce the referral 7 of business reimbursable under a federal health benefits program. The offense is a 8 felony punishable by fines of up to $25,000 and imprisonment for up to 5 years. 9 67. In accordance with the Anti-Kickback Statute, Medicare regulations 10 directly prohibit providers from receiving remuneration paid with the intent to induce 11 referrals or business orders, including the prescription of pharmaceuticals. 12 C.F.R. § 1001.952(f). Such remuneration is a kickback when paid to induce the writing 13 of prescriptions. 14 expenses by causing medically unnecessary expenditures. Kickbacks also compromise a 15 physician’s judgment causing him/her to consciously or subconsciously select drug 16 regimens based on his/her financial interest rather than the patient’s medical need. 17 68. See 42 Kickbacks increase government-funded health benefit program The Medicare Anti-Kickback Statute contains statutory exceptions and 18 certain regulatory “safe harbors” that exclude certain types of conduct from the reach of 19 the statute. 20 regulatory safe harbors protects the Defendant’s conduct in this case. 21 69. See 42 U.S.C. § 1320a-7(b)(3). None of the statutory exceptions or The Balanced Budget Act of 1997 added administrative civil penalties of 22 $50,000 for each act violating the Anti-Kickback Statute, as well as an assessment of not 23 more than three times the amount of remuneration offered, paid, solicited, or received, 24 without regard to whether a portion of that amount was offered, paid, or received for a 25 lawful purpose. See 42 U.S.C. § 1320a-740(7). 26 70. More recently, the Patient Protection and Affordable Care Act (“PPACA”), 27 Public Law No. 111-148, Sec. 6402(g), amended the Medicare Anti-Kickback Statute to 28 specifically allow violations of its “anti-kickback” provisions to be enforced under the Case No. 10-cv-03165 GHK (SSx) 18 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 24 of 141 Page ID #:1296 1 False Claims Act. 2 requirement” to make clear that violations of the Social Security Act’s anti-kickback 3 provisions, like violations of the False Claims Act, may occur even if an individual does 4 not have “actual knowledge” or “specific intent to commit a violation.” Id. at Sec. 5 6402(h). 6 71. The PPACA also amended the Social Security Act’s “intent As detailed below, Celgene’s marketing of Thalomid and Revlimid 7 repeatedly violated provisions of the Anti-Kickback Statute, which in turn violated the 8 False Claims Act. Celgene’s kickbacks and incentives induced physicians to prescribe 9 Thalomid and Revlimid when they otherwise would not have, and many of those 10 prescriptions were paid for by Medicare, Medicaid and other government funded health 11 insurance programs as well as by private insurers, including those in California. 12 F. Stark Law - The Medicare/Medicaid Self-Referral Statute 13 72. The Medicare/Medicaid Self-Referral Statute, 42 U.S.C. § 1395nn, et seq., 14 known as the “Stark” law, prohibits a pharmaceutical manufacturer from paying 15 remuneration to physicians for referring Medicare and Medicaid patients to the 16 manufacturer for certain “designated health services,” including drug prescriptions, 17 where the referring physician has a nonexempt “financial relationship” with that 18 manufacturer. 42 U.S.C. §§ 1395nn(a)(1), (h)(6). The Stark law provides that the 19 manufacturer shall not cause to be presented a Medicare or Medicaid claim for such 20 prescriptions. Stark also prohibits payment of claims for prescriptions rendered in 21 violation of its provisions. 42 U.S.C. §§ 1395nn(a)(1), (g)(1). 22 73. Celgene’s marketing of Thalomid and Revlimid repeatedly violated the 23 Stark law, which in turn violated the False Claims Act, because Celgene’s unlawful 24 payments and services to prescribing physicians induced those physicians to prescribe 25 these drugs when they otherwise would not have done so. Many of those prescriptions 26 were paid for by government funded health insurance programs. 27 28 Case No. 10-cv-03165 GHK (SSx) 19 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 25 of 141 Page ID #:1297 1 G. The California Insurance Frauds Prevention Act 2 74. The California Insurance Frauds Prevention Act prohibits the knowing 3 employment of “runners, cappers, steerers or other persons to procure clients or patients 4 ... to perform or obtain services or benefits under a contract of insurance or that will be 5 the basis for a claim against an insured individual or his or her insurer.” Cal. Ins. Code § 6 1871.7(a). It also establishes liability for parties that violate “Section 549, 550, or 551 7 of the Penal Code….” Cal. Ins. Code § 1871.7(b). 8 75. California Penal Code § 549 makes it illegal for any firm or corporation to 9 “solicit[], accept[],or refer[] any business to or from any individual or entity with the 10 knowledge that, or with reckless disregard for whether” that individual or entity will 11 present or cause to be presented any false or fraudulent claim for payment of a 12 healthcare benefit. 13 76. California Penal Code § 550 makes it illegal for any firm or corporation to 14 “[k]nowingly present or cause to be presented any false or fraudulent claim for the 15 payment of a loss or injury, including payment of a loss or injury under a contract of 16 insurance”; “[k]nowingly prepare, make, or subscribe any writing, with the intent to 17 present or use it, or to allow it to be presented, in support of any false or fraudulent 18 claim”; and “[k]nowingly make or cause to be made any false or fraudulent claim for 19 payment of a health care benefit.” Cal. Penal Code §§ 550 (a)(1), (5), and (6). 20 77. California Penal Code § 550 also makes it illegal for any firm or 21 corporation knowingly to present, or to assist or conspire to “[p]resent or cause to be 22 presented any written or oral statement as part of, or in support of or opposition to, a 23 claim for payment or other benefit pursuant to an insurance policy, knowing that the 24 statement contains any false or misleading information concerning any material fact”: 25 and to “[p]repare or make any written or oral statement that is intended to be presented 26 to any insurer or any insurance claimant in connection with, or in support of or 27 opposition to, any claim or payment or other benefit pursuant to an insurance policy, 28 Case No. 10-cv-03165 GHK (SSx) 20 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 26 of 141 Page ID #:1298 1 knowing that the statement contains any false or misleading information concerning any 2 material fact.” Cal. Penal Code §§ 550 (b)(1), (2). 3 78. The legislative findings and declarations associated with the California 4 Insurance Frauds Prevention Act make clear that the Legislature was concerned with 5 healthcare fraud: “Health insurance fraud is a particular problem for health insurance 6 policyholders. Although there are no precise figures, it is believed that fraudulent 7 activities account for billions of dollars annually in added health care costs nationally. 8 Health care fraud causes losses in premium dollars and increases health care costs 9 unnecessarily.” Cal. Ins. Code § 187l(h). 10 11 V. SPECIFIC ALLEGATIONS OF CELGENE’S FALSE CLAIMS A. 12 13 Celgene’s Prescription Drugs Thalomid and Revlimid 1. 79. Thalomid’s FDA-Approved Uses and Restrictions Initially, Celgene applied for, and in 1998 received, FDA approval for 14 thalidomide, marketed by Celgene under the brand name Thalomid, for the treatment of 15 ENL, a rare skin condition associated with leprosy. The drug was, and is, approved to 16 treat “cutaneous manifestations of moderate to severe” ENL, as well as to prevent and 17 suppress recurrences of ENL on human skin. ENL is an exceedingly uncommon skin 18 condition that affects very few Americans each year. According to the Health Resources 19 and Service Administration, a division of HHS, there were a mere 137 new cases of 20 leprosy in America in 2006 and there were a total of 1,600 cases from 1998 through 21 2009. Thus, the number of patients suffering from moderate to severe ENL (most ENL 22 is mild) – a subset of the total leprosy population – is quite small. 23 80. Celgene later applied for, and received in May 2006, FDA approval for 24 Thalomid, when used in combination with the drug dexamethasone, for treatment of 25 newly diagnosed MM. MM is a cancer of blood cells, like leukemia. An MM patient’s 26 plasma cells grow uncontrolled in the bone marrow, destroying the bone and eventually 27 reaching the peripheral circulation. MM can cause patients to experience increased 28 bleeding, increased rates of infection, kidney damage, bone disease, and death. Case No. 10-cv-03165 GHK (SSx) 21 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 27 of 141 Page ID #:1299 1 81. Thalomid is approved only in combination with another drug, 2 dexamethasone, for patients who have newly diagnosed MM. Thalomid has never been 3 approved as a solo or “monotherapy” treatment for MM. This means that Thalomid 4 cannot be prescribed in conjunction with a drug other than dexamethasone or by itself to 5 treat MM. In addition, Thalomid has never received FDA approval for treatment of 6 patients with MM who have received any prior drug therapy. 7 8 82. From 1998 to the present day, however, Celgene marketed Thalomid for several other diseases, including: 9 i) bladder cancer; 10 ii) breast cancer; 11 iii) brain cancer; 12 iv) cervical cancer; 13 v) colorectal cancer; 14 vi) esophageal cancer; 15 vii) leukemia (including, but not limited to, chronic lymphocytic leukemia 16 (“CLL”)); 17 viii) lymphoma; 18 ix) melanoma; 19 x) prostate cancer; 20 xi) pancreatic cancer; 21 xii) renal (i.e., kidney) cancer; 22 xiii) thyroid cancer; 23 xiv) new onset multiple myeloma (prior to the FDA’s May 26, 2006 approval of 24 Thalomid to treat new onset (only) of this disease); 25 xv) 26 xvi) myelodysplastic syndromes (MDS); 27 xvii) ovarian cancer; and 28 xviii) uterine cancer. multiple myeloma, not in combination with the drug dexamethasone; Case No. 10-cv-03165 GHK (SSx) 22 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 28 of 141 Page ID #:1300 1 2 83. prescriptions can cost as much as $24,000 per year per patient. 3 4 While the price of Thalomid varies by dose and duration, Thalomid 2. 84. Revlimid’s FDA-Approved Uses and Restrictions Celgene sought and received on December 27, 2005, FDA approval for 5 lenalidomide, marketed by Celgene under the brand name Revlimid, for an extremely 6 narrow indication: the treatment of patients with transfusion-dependent anemia due to 7 low or intermediate risk MDS only when associated with a deletion 5q cytogenic 8 abnormality (i.e., deletion of the long arm of chromosome 5) with or without additional 9 cytogenic abnormalities. MDS refers to a group of blood disorders that prevents human 10 bone marrow from producing healthy blood cells. This is largely a disease of older 11 adults. Although MDS includes a range of subtypes, Revlimid is indicated only for the 12 specific MDS-subtype of “low or intermediate risk” with “a deletion 5q cytogenic 13 abnormality with or without additional cytogenic abnormalities.” Stated differently, 14 Revlimid is not indicated, and has never been indicated, for MDS patients (a) who do 15 not have a deletion 5q cytogenic abnormality or (b) who have high risk MDS. Only 16 about 20% to 30% of patients with MDS have a deletion 5q cytogenic abnormality. 17 According to the Leukemia & Lymphoma Society, there are roughly 11,400 new cases 18 of MDS (all types) each year, which equates to only 2,300 to 3,400 new cases of MDS 19 with a deletion 5q cytogenic abnormality each year. 20 85. In June 2006, Celgene secured FDA approval for Revlimid when taken in 21 combination with dexamethasone for MM patients who have received at least one prior 22 therapy. Unlike Thalomid, Revlimid is not approved for newly diagnosed MM, but only 23 for those who have already received another treatment other than Revlimid. Although 24 the company has attempted to obtain approval for Revlimid to treat newly diagnosed 25 MM, it has been unsuccessful. On or around June 21, 2012, Celgene was forced to 26 withdraw its application in Europe to have Revlimid approved for use as initial therapy 27 for newly diagnosed myeloma patients and elected to postpone any application for the 28 Case No. 10-cv-03165 GHK (SSx) 23 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 29 of 141 Page ID #:1301 1 same to the FDA. Celgene’s European application was withdrawn due to concerns 2 raised by European regulators about the link between Revlimid and secondary cancers. 3 86. Despite Revlimid’s very narrow indication, Celgene marketed and 4 continues to market the drug for all types of MDS, as well as a host of other off-label 5 uses, including: 6 i. brain cancer; 7 ii. leukemia (including, but not limited to, CLL); 8 iii. lymphoma; 9 iv. myelofibrosis; 10 v. multiple myeloma (prior to Revlimid receiving FDA approval to treat this 11 disease under specified circumstances); 12 vi. multiple myeloma not in combination with the drug dexamethasone; 13 vii. newly-diagnosed multiple myeloma; 14 viii. prostate cancer; and 15 ix. stem-cell transplant maintenance therapy after stem cell transplant. 16 87. Revlimid is extremely expensive; prescriptions can cost as much as 17 $120,000 per year per patient. 18 3. 19 a. 20 21 Safety Issue: FDA Warnings Concerning Potentially Fatal Side Effects of Thalomid and Revlimid 88. History of Thalomid Thalidomide, which Celgene later marketed as Thalomid, was first 22 manufactured in 1957 by Chemie Grünenthal, a German pharmaceutical company that 23 hired several Nazi doctors and scientists. For example, it employed Martin Staemmler, a 24 leading proponent of the Nazi “racial hygiene” program who, following Germany’s 25 invasion of Poland, worked with the SS on its population policy. He was Grünenthal’s 26 head of pathology at the time it sold thalidomide. Grünenthal also employed Otto 27 Ambros, one of the four inventors of the nerve gas sarin. In 1948, Ambros was found 28 guilty at Nuremberg of mass murder and enslavement and sentenced to eight years in Case No. 10-cv-03165 GHK (SSx) 24 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 30 of 141 Page ID #:1302 1 prison. Ambros was the chairman of Grünenthal’s advisory committee at the time it 2 developed thalidomide. 3 89. In 1958, thalidomide was used throughout Europe and Canada to treat 4 morning sickness in pregnant women. 5 identified as the cause of between 10,000 and 20,000 serious birth defects, including 6 severely deformed, or all together missing, limbs. Thalidomide was not approved by the 7 FDA during this period, but samples of thalidomide were blamed for at least 17 cases of 8 severe birth defects in America. 9 90. By 1961, however, thalidomide had been Specifically in response to the horror stories concerning birth defects from 10 thalidomide, in 1962 Congress passed the Kefauver Harris Amendment, which for the 11 first time required pharmaceutical companies to demonstrate a drug’s efficacy in 12 addition to safety to the FDA in order to obtain approval to market any new drug in the 13 United States. This legislation also required drug advertisements to disclose complete 14 information about potential side effects to consumers. 15 91. More than thirty years later, in 1998 when the FDA approved thalidomide 16 (now marketed as Thalomid) for treatment of ENL, the FDA required Celgene to take 17 multiple precautions to prevent Thalomid from causing severe birth defects. In addition 18 to requiring Celgene to place a black-box warning on Thalomid’s product labeling, the 19 FDA required Celgene to take the step of creating a distribution system to prevent fetal 20 exposure to Thalomid. 21 92. Specifically, as a condition of FDA approval, Celgene created the “System 22 for Thalidomide Education and Prescribing Safety” (“S.T.E.P.S.”), which requires all 23 Thalomid-prescribing physicians to register with Celgene. 24 prescribing physicians to counsel patients on the risks of sexual activity during 25 Thalomid use. Before a physician can prescribe Thalomid, the physician must notify 26 Celgene through an automated system that he or she has counseled the patients on the 27 risks of birth defects; then a Thalomid prescription is authorized by Celgene. 28 Case No. 10-cv-03165 GHK (SSx) 25 THIRD AMENDED COMPLAINT It also requires all Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 31 of 141 Page ID #:1303 1 93. As Revlimid is in the same class of drugs as Thalomid, it too can cause 2 birth defects. 3 Revlimid when taken during pregnancy recommends that all female patients of 4 childbearing potential obtain two negative pregnancy tests before starting Revlimid and 5 use two forms of contraception during and for four weeks after taking Revlimid. The 6 black box warning for birth defects is as follows: 7 8 9 10 11 12 13 14 15 16 The black box warning concerning risks of birth defects caused by WARNING: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or death to a developing baby. In women of childbearing potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Women of childbearing potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid fetal exposure to lenalidomide, REVLIMID is only available under a restricted distribution program called “RevAssist®” (5.2). Information about the RevAssist program is available at www.REVLIMID.com or by calling the manufacturer’s toll-free number 1888-423-5436. 94. When the FDA first approved Revlimid in December 2005, it mandated a 17 distribution system similar to S.T.E.P.S. called RevAssist. Because of the S.T.E.P.S. 18 and RevAssist programs, Celgene has detailed records regarding every Thalomid and 19 Revlimid prescription including all of the prescriptions submitted to Medicare, 20 Medicaid, TRICARE, the VA and other government payors. As explained in more 21 detail below, Celgene ultimately manipulated the cumbersome nature of S.T.E.P.S. and 22 RevAssist to cause Medicare, Medicaid, and other government funded programs to 23 cover the high-cost of off-label Thalomid and Revlimid prescriptions. 24 b. 25 26 95. Thalomid’s and Revlimid’s Black Box Warnings Concerning Venous Thromboembolism Cancer patients, including those with MM, already have an increased risk 27 of developing venous thromboembolism (“VTE”), which are blood clots that form 28 within a vein. According to a 2005 article entitled Deep Vein Thrombosis in Cancer: the Case No. 10-cv-03165 GHK (SSx) 26 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 32 of 141 Page ID #:1304 1 scale of the problem and approaches to management published in the Annals of 2 Oncology, VTE is found at autopsy in at least 50% of cancer patients. Annals of 3 Oncology, 16(5): 696-701 (May 2005). 4 96. VTEs are called deep venous thrombosis (“DVT”s) when they form within 5 the deep veins of the leg, the pelvic veins, or other veins. When the clots travel to the 6 lungs, they are called pulmonary embolisms (“PE”s). 7 function and can be fatal. Short of death, VTEs may cause heart complications, ulcers, 8 and vein damage which can permanently impair blood flow. 9 97. PEs can compromise lung Both Thalomid and Revlimid exacerbate the risk of VTEs in cancer 10 patients. After Thalomid received its MM indication in May 2006, the FDA required 11 Celgene to add the following black-box warning: 12 18 The use of Thalomid® (thalidomide) in multiple myeloma results in an increased risk of venous thromboembolic events, such as deep venous thrombosis and pulmonary embolus. This risk increases significantly when thalidomide is used in combination with standard chemotherapeutic agents including dexamethasone. In one controlled trial, the rate of venous thromboembolic events was 22.5% in patients receiving thalidomide in combination with dexamethasone compared to 4.9% in patients receiving dexamethasone alone (p = 0.002). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Preliminary data suggest that patients who are appropriate candidates may benefit from concurrent prophylactic anticoagulation or aspirin treatment. 19 98. 13 14 15 16 17 Revlimid carries a similar black-box warning concerning risk of VTEs in 20 MM patients. The following is the FDA required black box warning for Revlimid 21 concerning VTEs: 22 23 24 25 26 27 28 WARNING: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM … Deep Vein Thrombosis and Pulmonary Embolism REVLIMID has demonstrated an increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolic events. The decision to take prophylactic Case No. 10-cv-03165 GHK (SSx) 27 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 33 of 141 Page ID #:1305 1 2 3 measures should be done carefully after an assessment of an individual patient’s underlying risk factors. 99. Because Thalomid was indicated solely for ENL from 1998 to 2006, 4 Thalomid’s product information did not carry a black-box warning specifically 5 concerning VTEs in MM patients during that period. Moreover, because Thalomid and 6 Revlimid are only FDA approved for MM and MDS, neither drug carries warnings 7 concerning the potential risks of VTEs in other forms of cancer. 8 100. As a result, doctors that prescribed Thalomid for MM prior to its receiving 9 an MM indication in 2006 were not specifically warned by the label of the risks of VTEs 10 in MM patients taking Thalomid. Furthermore, at all relevant times, as discussed below, 11 physicians prescribing Thalomid or Revlimid for cancers other than MM and for MDS 12 were not, and are not, warned about the drugs’ association with VTEs in various types of 13 other cancers. 14 c. Thalomid’s and Revlimid’s Additional Safety Risks 15 101. In addition to the risk of potentially fatal blood clots, Thalomid and 16 Revlimid can cause other serious side effects including hematologic toxicity, peripheral 17 neuropathy, and Stevens-Johnson Syndrome. 18 malignancies. 19 patients to these risks. Revlimid can also cause new Celgene’s off-label marketing of Thalomid and Revlimid exposed 20 102. Revlimid’s package insert includes a black-box warning concerning 21 hematologic toxicity ̶ specifically neutropenia and thrombocytopenia. Patients with 22 neutropenia have low white blood cell counts, which can seriously compromise their 23 ability to fight off infections. Thrombocytopenia sufferers, by contrast, have low blood 24 platelet levels, which can make it difficult for the blood to clot. Thrombocytopenia can 25 cause patients to suffer hemorrhages, which can lead to death. The black box warns that 26 patients taking Revlimid can suffer from these types of hematologic toxicity: 27 28 WARNING: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM Case No. 10-cv-03165 GHK (SSx) 28 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 34 of 141 Page ID #:1306 1 2 3 4 5 6 7 8 …Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 [on a scale of 1-4] hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)]. 9 10 103. Revlimid and Thalomid can also cause peripheral neuropathy (i.e., nerve 11 damage), which can be severe and potentially permanent. Finally, both drugs can cause 12 Stevens-Johnson Syndrome, a painful and dangerous condition causing skin to necrose 13 and peel off, as in a third-degree burn. Stevens-Johnson Syndrome can be fatal. 14 104. On April 8, 2011, the FDA issued a safety announcement concerning 15 Revlimid’s potential for causing new malignancies. The FDA announced that clinical 16 trials conducted both within and outside the United States “found that patients treated 17 with Revlimid (lenalidomide) may be at an increased risk of developing new types of 18 cancer compared to patients who did not take the drug.” The cancers associated with 19 Revlimid and Thalomid use include acute myelogenous leukemia (AML) and B-cell 20 lymphoma. In July of 2013, the FDA ordered Celgene to stop a Phase III clinical trial of 21 Revlimid for chronic lymphocytic leukemia (CLL) in elderly patients because of an 22 imbalance of deaths among study participants - 34 deaths in the Revlimid group 23 compared to 18 deaths in the chlorambucil (a chemotherapeutic agent) group. 24 25 26 B. Celgene Engaged In a Wide Variety of Illegal Marketing Schemes To Promote Thalomid and Revlimid For Off-Label Use 1. Celgene Gave Its Staff Purposefully Misleading Titles 27 105. When Relator was hired at Celgene in April 2001 she was immediately 28 directed by Celgene to commence marketing Thalomid to physicians for off-label uses. Case No. 10-cv-03165 GHK (SSx) 29 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 35 of 141 Page ID #:1307 1 To accomplish this task, Relator and other Celgene sales professionals were dispatched 2 to physicians under false pretenses. 3 106. Celgene gave Relator the title “Immunology Specialist,” which indicated to 4 physicians that Relator was a medical professional, as opposed to a sales representative. 5 Relator, however, has no formal medical training and never studied immunology. 6 Nonetheless, Celgene required Relator to hold herself out as competent to educate 7 physicians and other medical practitioners in immunology. 8 107. Celgene also gave Relator the title “S.T.E.P.S. Field Coordinator” – a 9 reference to Thalomid’s FDA-mandated education, recordkeeping, and distribution 10 system – and dispatched her to medical practices under the guise of assisting physicians 11 with the FDA-required S.T.E.P.S. program. 12 representatives’ purported assistance with S.T.E.P.S. was a “bait-and-switch.” Celgene 13 used the program as an additional opportunity to off-label market Thalomid to captive 14 physicians who required help in complying with S.T.E.P.S. In reality, Relator’s and other sales 15 108. More specifically, Celgene tasked Relator and the other 100-plus S.T.E.P.S. 16 Field Coordinators across the country to physicians’ offices where they instructed 17 physicians on procedures for registering themselves and their patients with S.T.E.P.S. 18 and the requirement to contact Celgene directly each time the physician wrote a 19 Thalomid prescription. It was during these S.T.E.P.S. meetings with physicians that 20 Relator marketed, at Celgene’s direction, Thalomid for off-label uses. 21 109. In or about December 2004, Celgene changed Relator’s title from 22 Immunology Specialist to Hematology Oncology Consultant (“HOC”). Relator’s job 23 duties stayed exactly the same, but because Thalomid was being marketed for both 24 hematologic malignancies and solid tumors, Celgene believed the HOC title more 25 accurately reflected the message it intended its sales force to communicate to physicians. 26 Again, while Relator has no formal medical training, Celgene required and continued to 27 require her to hold herself out to physicians as learned in both hematology and oncology. 28 Case No. 10-cv-03165 GHK (SSx) 30 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 36 of 141 Page ID #:1308 1 In reality, Relator was a sales representative and her compensation depended 2 significantly upon her ability to market Thalomid and Revlimid to physicians. 3 2. Celgene Rewarded Its Sales Force For Their Off-Label Sales 4 110. Relator and other sales personnel were, and are, rewarded by Celgene for 5 their off-label sales. Celgene’s compensation and bonus structure incentivizes its sales 6 force to meet or exceed certain benchmarks in drug sales. On March 23, 2003, Celgene 7 distributed an internal memorandum to Relator and other Celgene sales professionals 8 from Dwight D’Iorio, Celgene’s then-National Executive Director of Sales, stating that 9 Relator and her colleagues would have “the opportunity to earn additional bonus money 10 with each additional sales level achieved,” at a time when Thalomid was approved only 11 for a single, rare indication related to leprosy. 12 111. Relator received Celgene stock options, cash bonuses, and vacations based 13 on her off-label sales of Thalomid and Revlimid. In 2003, Relator was a member of the 14 “Diamond Club” which, according to Celgene management, “represents the pinnacle of 15 success at Celgene.” Diamond Club members are “in the top 15% of performers” based 16 on drug sales; they received a Movado watch enhanced with a diamond for each 17 additional year the salesperson remains a Diamond Club member. 18 112. Celgene holds an annual “Chairman’s Challenge,” a bonus program that 19 rewards sales personnel for gross on-label and off-label Thalomid and Revlimid sales 20 and each salesperson’s ability to exceed certain sales benchmarks. A March 2003 21 Chairman’s Challenge announcement from Dwight D’Iorio states, “[a]s promised at the 22 National Sales Meeting there will be an additional bonus opportunity if we achieve an 23 even higher level of sales success.” 24 113. Even when Celgene faced heightened scrutiny relating to its bonus 25 structure, it pretended to curb its illegal practices but, in reality, continued them. At the 26 2005 National Sales Meeting, Celgene’s Senior Vice President of Sales and Marketing, 27 Francis Brown (“Brown”) told Celgene’s sales force that they would no longer be 28 compensated for Thalomid sales. Case No. 10-cv-03165 GHK (SSx) In 2005 Celgene anticipated FDA approval of 31 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 37 of 141 Page ID #:1309 1 Revlimid and, according to Brown, the Company was worried that the FDA would 2 question Thalomid’s high volume of sales because Thalomid was then only approved for 3 ENL. Brown said that Celgene intended to tell the FDA that Celgene’s sales force was 4 paid for administering the S.T.E.P.S. distribution system, not for Thalomid sales. This 5 would indicate to the FDA that Celgene’s sales force was not paid or incentivized to 6 market Thalomid off-label. Brown also told Celgene sales personnel that not providing 7 bonuses for off-label sales would show the FDA that sales representatives were not 8 directed to off-label market. Brown said this would “protect” the sales representatives 9 and Celgene would be able to show the FDA that the Company was not “out of line.” 10 11 12 13 14 15 114. Despite these statements, Celgene did provide bonuses based on Thalomid sales in 2005. 115. In reality, Celgene had misbranded Thalomid for years and rewarded its sales force handsomely for their misbranded sales. 3. Celgene Was Aware Of The Serious Health Risks Caused By Thalomid And Revlimid But Trained Its Sales Force To Conceal The Facts 16 116. As explained above, Thalomid and Revlimid present a variety of serious 17 risks to patients. Celgene was well aware of these risks but trained its sales force to 18 conceal these risks from patients and doctors. 19 117. At the time Celgene promoted and marketed Thalomid and Revlimid off- 20 label, and long before the FDA issued its black box warning about VTEs in 2006, the 21 Company was aware of the elevated risks of VTE that these drugs posed to cancer 22 patients. Celgene knew about trials showing an increased incidence of VTEs in cancer 23 patients taking Thalomid and received reports from the Company’s sales personnel that 24 doctors were concerned about prescribing Thalomid to their cancer patients. 25 118. Shortly after Relator joined Celgene in 2001, she participated in a 26 mandatory internal conference call with all of the Company’s sales professionals and 27 other employees. This training call was conducted by the pharmacists, Dr. and Dr. Long 28 (a married couple), who were retained by the Company to discuss risks associated with Case No. 10-cv-03165 GHK (SSx) 32 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 38 of 141 Page ID #:1310 1 Thalomid. During this call, the Longs discussed the risks posed by Thalomid, but 2 instructed the sales professionals to withhold this information and not mention the risks 3 to doctors. The Celgene sales professionals were told that doctors would see the DVTs 4 and PEs as side effects of MM in patients, and to address the issue by simply stating that 5 people with MM have a greater chance of developing VTE, rather than warning the 6 doctors that use of Thalomid by patients with MM would increase this risk. Relator was 7 so concerned that immediately after this mandatory call ended, she talked to a fellow 8 West Region sales representative who told her to not worry. 9 119. As concern grew about DVTs and PE’s, Celgene addressed drug trials and 10 doctors’ concerns about Thalomid in education and training materials it distributed to its 11 sales personnel, including a document entitled “Thromboembolism Backgrounder” 12 distributed in 2004. 13 Company, Celgene acknowledged that VTEs had been reported when thalidomide first 14 began to be prescribed for MM, prostate cancer and other types of cancer, starting 15 around 2000. In fact, as noted in the Backgrounder, “[b]ecause of a high incidence of 16 this effect, some clinical trials with thalidomide were suspended.” In that document, which was sent directly to Relator by the 17 120. The Backgrounder also discussed the results of a survey by the Canadian 18 Coordinating Office for Health Technology Assessment, which published the results in 19 January 2004: 20 21 22 23 24 25 26 27 This report noted several studies where a high incidence of thromboembolism (15% to 50%) was reported. In a few trials, thromboembolism was reported in 5% to 10% of patients. … A study by Bowcock et al. (2002) reported thromboembolism in 7 of 23 patients (30%) who received thalidomide as a single agent. Several reports have described thromboembolism in patients who received thalidomide as part of treatment for prostate cancer. For example, in a study by Home et al. (2003), venous thromboembolism was reported in 0% of patients who received docetaxel alone, vs. 19% of patients who received docetaxel and thalidomide. 28 Case No. 10-cv-03165 GHK (SSx) 33 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 39 of 141 Page ID #:1311 1 2 3 VTE has also been reported in patients who received thalidomide as treatment for other cancer types, including renal cell carcinoma, myelodysplastic syndrome, and mantle cell lymphoma. 4 121. Celgene sold Thalomid in Australia through its business partner Pharmion 5 Corporation (“Pharmion”). The labeling and other materials distributed by Celgene and 6 Pharmion prior to 2005 in Australia recognized the VTE issue. 7 January 2004 Thalidomide Pharmion Information Brochure stated that “[i]n malignant 8 conditions … patients are predisposed to a hypercoaguable state” and that “[c]aution 9 should be used when Thalomid is combined with chemotherapy, as venous 10 thromboembolism is a potential complication …. An unexpectedly high risk of venous 11 thromboembolism has been observed when Thalomid is combined with chemotherapy 12 for newly diagnosed patients with myeloma.” This same document also cites studies 13 showing the potential for experiencing thrombotic events is particularly acute when 14 Thalomid is used concomitant with vincristine, doxorubicin and dexamethasone. For example, the 15 122. Despite numerous studies showing increased risk of VTE in cancer patients 16 taking thalidomide, Celgene told its sales professionals that there was no cause for alarm 17 or need to warn doctors. 18 development of VTE with thalidomide use in cancer patients are not clearly 19 understood.” Celgene further stated that: 20 In the Backgrounder, Celgene stated “The reasons for 22 Several reports have noted that thromboembolism is relatively uncommon when thalidomide is given as a single-agent therapy, and that the greatest incidence has come when thalidomide is used in combination with chemotherapy and/or corticosteroids. 23 123. In a section of the Backgrounder headed “Management,” Celgene suggested 24 that warfarin be proposed in conjunction with thalidomide to reduce the risk of VTE. 25 The Backgrounder stated: 21 26 27 28 Management of patients who have thromboembolic episodes in association with thalidomide use is similar to approaches described earlier in this program. Anticoagulation therapy (heparin, with or without warfarin) plus other approaches used in treatment of DVT and/or PE may be provided. Case No. 10-cv-03165 GHK (SSx) 34 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 40 of 141 Page ID #:1312 1 2 3 4 5 6 7 When anticoagulant therapy is provided, DVT may not require discontinuance of thalidomide. Thalidomide has been resumed safely, in combination with warfarin, in patients who experienced thrombolic events. Some clinicians have provided warfarin prophylactically to cancer patients who are treated with thalidomide. The combined use of these agents may decrease the incidence of thromboembolism; however, this has yet to be established through controlled clinical trials. 8 124. In short, Celgene knew, but instructed its sales personnel not to warn 9 doctors, about the increased risk of developing VTE in cancer patients taking 10 thalidomide. If doctors raised this risk as an issue, Celgene trained its sales personnel to 11 discount the risk and suggest that the doctors prescribe an anticoagulation therapy such 12 as warfarin to purportedly decrease the risk of VTE. Celgene’s training of its sales 13 representatives to encourage warfarin use began as early as 2001 during the mandatory 14 conference call with the Drs. Long discussed above. 15 125. Celgene also told its sales personnel to propose the use of baby aspirin if a 16 doctor raised the issue of VTE. As purported support for that instruction, Celgene 17 provided its sales personnel with copies of a summary of an article by Mohamad A. 18 Hussein, titled “Thromboembolism Risk Reduction In Multiple Myeloma Patients 19 Treated With Immunomodulatory Drug Combinations,” which discussed the results of 20 various trials. Celgene provided its sales personnel a summary of the Hussein article. 21 (Celgene later hired Dr. Hussein.) In the summary, Celgene argued that aspirin reduced 22 the incidence of VTE. The Hussein article concluded: 23 Strategies to reduce the risk of VTE associated with thalidomide and 24 lenalidomide combinations while maintaining activity should consider the 25 prophylactic use of anti-coagulants. There are no randomized trials to favor 26 one anticoagulation agent or regimen over another in this setting. 27 126. What Celgene did not tell its sales personnel was that the American 28 Academy of Chest Physicians – in its contemporaneous (2004) Guidelines – states that Case No. 10-cv-03165 GHK (SSx) 35 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 41 of 141 Page ID #:1313 1 aspirin should not be used for VTE prophylaxis for any patient group (the Academy 2 rates this recommendation 1A, its strongest rating). Nor did Celgene tell its sales 3 personnel that the American College of Physicians (an association of internists) has 4 never recognized aspirin as appropriate for thromboprophylaxis. Celgene also failed to 5 provide an objective analysis of the various studies discussed in the Hussein article and 6 to discuss any of the problems of those studies (such as their small size) or other 7 problems (such as the failure to provide information on the number of patients or length 8 of the trial). 9 127. Thus, Celgene directed its sales representatives to recommend that doctors 10 couple Thalomid with aspirin as a way to reduce the risk of developing VTE. The 11 Company suggested this multiple times including the 2001 mandatory conference call 12 with the Drs. Long discussed above. This put patients’ lives and health at risk. 13 128. At the time that Celgene was marketing Revlimid off-label, Celgene knew 14 that the drug could cause other cancers, particularly in patients with newly-diagnosed 15 MM. Clinical trials had demonstrated an increased risk of acute myelogenous leukemia, 16 myelodysplastic syndromes, and Hodgkin’s lymphoma. As with VTEs, rather than 17 warning physicians about these risks, Celgene instructed Relator and others to withhold 18 this information. Relator followed these instructions and cannot recall ever informing a 19 single doctor about these risks. Moreover, Celgene’s Director of Regulatory Affairs, 20 William Woolever, often spoke at National Sales Meetings. During these meetings, he 21 emphasized that sales representatives needed to disclose only risks in the label, and later, 22 in the black box. 23 24 25 26 129. In May 2012, the FDA announced that information about this risk posed by Revlimid would be added to the drug’s label. 4. Celgene Repeatedly Trained Relator and Other Sales Personnel To Market Thalomid and Revlimid Off-Label And Then Managed Them To Ensure That They Were Marketing Off-Label 27 130. From the day Relator began at Celgene in 2001, the company began 28 training her to market Thalomid, and later Revlimid, off-label. The training continued Case No. 10-cv-03165 GHK (SSx) 36 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 42 of 141 Page ID #:1314 1 throughout her tenure at Celgene. 2 approved of the off-label marketing. 3 a. 4 The company’s management also observed and Celgene Never Trained Its Sales Force To Market Thalomid On-Label 5 131. When Relator joined Celgene in April 2001, Thalomid was only approved 6 for treatment of ENL; it did not receive an additional indication until a full five years 7 later, in May 2006. Nevertheless, Celgene never provided Relator any information or 8 training concerning Thalomid’s use in ENL. Celgene never provided Relator with any 9 studies, pamphlets, or educational materials of any sort concerning the sole disease for 10 which Thalomid, at the time, was indicated. In her nearly twelve years at Celgene, 11 Relator never met a physician who, to her knowledge, treated ENL. Furthermore, on 12 average, a mere twelve new leprosy cases are treated in California each year, meaning 13 ENL patients are virtually non-existent in Relator’s sales territory. 14 132. When Relator first arrived at Celgene in 2001, she received some formal 15 classroom training on Thalomid and the micro-environment. Significantly, Celgene 16 provided her with a copy of a single patient case report by Dr. Bart Barlogie in which 17 Thalomid was used to treat MM. At the time, the FDA had only approved Thalomid for 18 the treatment of ENL. Celgene failed to train Relator about FDA rules and regulations 19 prohibiting off-label marketing. In fact, her then-managers Deena Harding and Jeff 20 Rowell told her that FDA limits on marketing only applied to large companies, like 21 Merck. 22 133. Celgene never informed Relator about the 1998 FDA warning letters. 23 Relator conducted her own research and asked about the FDA warnings during her 24 second or third job interview with her future managers Dwight D’Iorio and Deena 25 Harding. Ms. Harding told Relator that the April 21, 2000 warning letter was not 26 important, maintaining that the conduct at issue was limited to one sales representative 27 in the Pacific Northwest who failed to obtain a medical information request form. 28 Case No. 10-cv-03165 GHK (SSx) 37 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 43 of 141 Page ID #:1315 1 134. After her classroom training ended, Relator was required to accompany 2 Alana Torgelson, the fourth sales representative hired by Celgene, for a day. During this 3 training ride-along, Relator witnessed Ms. Torgelson converse with a doctor regarding a 4 patient suffering from renal cell cancer. The doctor asked Ms. Torgelson about the 5 proper Thalomid dose to treat renal cell cancer. Ms. Torgelson told him “400 [mg] is 6 what works” even though there is no evidence to support this dosage and there is no 7 FDA approval for renal cell cancer. 8 9 10 11 12 135. Relator then accompanied Ms. Torgelson on additional visits, and watched her promote Thalomid to treat other solid tumor cancers including cervical cancer. b. Celgene Trained Its Sales Force To Market Thalomid and Revlimid Off-Label at National Sales Meetings And By Bringing Relator and Other Sales Personnel To Corporate Headquarters 13 136. At national sales meetings and at intermittent visits to corporate 14 headquarters, Celgene coached Relator and other sales personnel to market its products 15 off-label. The company’s management then observed and evaluated Relator and other 16 sales personnel to ensure that they were implementing the off-label marketing plans. 17 137. For example, in 2004, at a Celgene National Sales Meeting at the Lacosta 18 Resort and Spa in Carlsbad, California, Celgene provided its sales force with a written 19 off-label marketing plan for Thalomid. In addition to Baer and Jackson, at that meeting, 20 Larry Bishop, the West Region Sales Director, was present and provided the Celgene 21 sales force with the “2004 Business Plan West Region (the ’Plan’).” The Plan focused 22 “solely on Thalomid,” and instructed sales personnel to, inter alia, “[e]mphasize MM, 23 MDS and targeted solid tumor activity1 on every [sales] call.” In other words, although 24 Thalomid (a) was not approved for MM2 at the time the memorandum was distributed, 25 26 27 28 1 “[T]argeted solid tumor activity” refers to non-hematological cancers. As stated above, Thalomid did not receive FDA approval for MM until May 2006. Even in 2006, however, Thalomid received only a narrow indication: for treatment of newly diagnosed MM, and only when taken in combination with the agent dexamethasone. 2 Case No. 10-cv-03165 GHK (SSx) 38 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 44 of 141 Page ID #:1316 1 (b) was and is not approved for MDS, and (c) was never approved for additional cancers, 2 Celgene’s senior management specifically directed Relator and her colleagues to market 3 Thalomid for those diseases “on every call.” 4 138. The 2004 Plan provides a “Market Analysis Summary” which reported that 5 Celgene’s West Region, through 2003, caused physicians to prescribe Thalomid to 230 6 brain cancer patients, 400 melanoma patients, 1000 MM patients, 730 MDS patients, 45 7 ovarian cancer patients, 250 prostate cancer patients, and 420 renal cell (i.e., kidney) 8 cancer patients. Celgene’s West Region was just one of Celgene’s sales districts. The 9 Plan also set “specific additional new patient goals, by malignancy.” 10 139. The 2004 Plan encouraged Celgene sales representatives to use numerous 11 off-label studies, journal articles and abstracts identified in the document when 12 marketing Thalomid for off-label uses. 13 140. The Plan reiterated and memorialized management’s previous (and 14 continuing) directives to off-label market Thalomid. 15 referenced the Plan. In Relator’s 2003 Performance Evaluation, completed in early 16 2004, Relator’s then-district sales manager, Jeff Rowell (“Rowell”), instructed Relator to 17 “Implement Larry Bishop’s Regional Plan by targeting the selected tumors with the 18 selected reference materials.” 19 Relator’s superiors, at times, 141. Relator successfully implemented the Plan. Every week, Celgene’s 20 national operations distributed spreadsheets summarizing Relator’s and other sales 21 representatives’ sales data. 22 labeled “Indication and Duration Reports,” which documented Relator’s total Thalomid 23 prescriptions for the current year as well as any “New [Thalomid] Patients” Relator 24 successfully obtained. Each spreadsheet broke these figures down by total numbers of 25 diagnosis and total Thalomid capsules prescribed. According to Relator’s April 16, 26 2004 sales report, as of April 2004, Relator had successfully caused physicians to 27 prescribe 11,116 Thalomid capsules for MM patients, 504 for renal cell cancer patients, 28 1,148 for MDS patients, 196 for melanoma patients, 168 for prostate cancer patients, Case No. 10-cv-03165 GHK (SSx) Most of these sales report spreadsheets included a tab 39 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 45 of 141 Page ID #:1317 1 112 for ovarian cancer patients, and 3,080 for patients suffering from “Other” ailments. 2 Strikingly, ENL – the only disease for which Thalomid was indicated, i.e., FDA 3 approved, until May 2006 – is not listed on any of these Celgene-generated spreadsheets. 4 142. Similarly, at the end of certain financial quarters, Celgene distributed 5 spreadsheets to Relator and her colleagues that included a tab labeled “Indication 6 Breakdown” and provided the “Total Business” for Thalomid in specific diseases. 7 According to Celgene’s spreadsheet for the first quarter of 2004, from the first quarter of 8 2003 through the first quarter of 2004, Celgene’s West Region sales force successfully 9 caused physicians to prescribe: 131,702 Thalomid capsules for MM patients, 13,608 for 10 MDS patients, and 1,484 for prostate cancer patients, and a total of 190,342 capsules for 11 all patients combined. Critically, this same spreadsheet indicates that zero physicians in 12 the region prescribed Thalomid for ENL. 13 143. At national sales meetings, Celgene presented patients taking Thalomid for 14 serious diseases that were outside Thalomid’s label to attest to the drug’s efficacy. 15 These individuals were introduced to the sales force both informally and on-stage. 16 Specifically, at the 2003 National Sales Meeting in West Palm Beach, a Celgene 17 employee introduced a patient suffering from melanoma, who spoke about her success 18 on Thalomid. 19 multiple myeloma at a National Sales Meeting. Following these patient presentations, a 20 Celgene employee routinely closed the meeting by emphasizing the importance of 21 providing off-label information to physicians so that similar patients could receive 22 Thalomid therapy. Celgene also presented a patient taking Thalomid as a single agent for 23 144. Celgene also routinely sent its sales force to the Company’s headquarters in 24 Summit, New Jersey to participate in off-label training sessions. For example, in or 25 about 2004, Larry Bishop, who authored the 2004 marketing plan, conducted a “Phase II 26 Training” to assist Celgene’s sales force in marketing Thalomid for a number of off- 27 label uses. Celgene required its entire sales force to attend this training. The Phase II 28 Training materials discussed Thalomid use in the following cancers: prostate, ovarian, Case No. 10-cv-03165 GHK (SSx) 40 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 46 of 141 Page ID #:1318 1 melanoma, renal, colorectal, brain, pancreatic, bladder, esophageal, gastric, testicular, 2 cervical, uterine, breast, and thyroid. Following the Phase II training session, Bishop 3 circulated a number of off-label studies concerning these diseases to sales 4 representatives for use in detailing physicians. Celgene routinely conducted mandatory 5 training seminars similar to Bishop’s Phase II Training at its headquarters in Summit, 6 New Jersey. 7 c. 8 Management Accompanied Relator and Other Sales Representatives on Sales Calls 9 145. Managers joined Relator and other sales representatives on their sales calls 10 at least once every three months to ensure that sales representatives were effectively 11 marketing Thalomid off-label. During Relator’s first four months at Celgene, in or 12 about July 2001, Relator’s then-district sales manager, Deana Harding, accompanied 13 Relator on a full day of sales calls. After those calls, Harding wrote in Relator’s 14 “Celgene Field Contact Report” that “I would like to hear you articulate the newly 15 diagnosed [MM] data next time we are together; as well as the thought leaders [sic] 16 dosing guidelines to move your MDs [doctors] forward.” Similarly, in a 2002 report, 17 Harding instructed Relator to “Brush up on your MDS and Figg data so that after 18 Myeloma you have an alternative message.” “Figg data” refers to a study concerning 19 Thalomid use in prostate cancer. Relator memorized portions of the Figg study in an 20 effort to promote Thalomid in prostate cancer. 21 146. Through discussions with fellow sales representatives, Relator has learned 22 that Celgene began to off-label market Thalomid almost immediately upon receiving 23 FDA approval. For instance, Linnie Burney, a fellow West Region sales representative 24 told Relator that in or about 1999 or 2000, Jerome Zeldis, Celgene’s then-Medical 25 Director, accompanied Burney on a sales call to Dr. Joyce O’Shaughnessy, a preeminent 26 breast cancer physician in Texas, in order to convince her to prescribe Thalomid to all of 27 her breast cancer patients. 28 Case No. 10-cv-03165 GHK (SSx) 41 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 47 of 141 Page ID #:1319 1 147. In Relator’s 2003 performance evaluation, Relator’s then-district sales 2 manager, Jeff Rowell, commented on a ride-along with Relator, writing, “You are not 3 afraid to seek to seek additional uses of Thalomid beyond Multiple Myeloma as 4 evidenced by seeing you discuss data on MDS, Renal Cell Carcinoma, Prostate Cancer, 5 Colorectal Cancer, Melanoma, and other tumor types [with physicians].”3 Based on this 6 and other performance measures, Rowell rated Relator’s 2003 job performance “EE” for 7 “Exceeds Expectations.” 8 148. Moreover, Relator’s managers conducted ride-alongs after Relator and 9 other sales representatives secured “unsolicited” off-label medical information request 10 forms signed by the physicians she called upon. 11 manager, she asked the physician whether he or she had received the off-label 12 information requested. As directed by Celgene, Relator often asked the physician for 13 assurances that he or she would prescribe Thalomid for off-label use. This showed 14 Relator’s manager that she was securing off-label information requests, and succeeding 15 in securing new prescriptions. When Relator returned with her 16 149. Similarly, as with Thalomid, Relator’s managers continued to conduct 17 routine “ride-alongs” to ensure that Relator and other sales staff effectively marketed 18 Revlimid for off-label uses. 19 accompanied her on several ride-alongs. 20 Michael Steinberg at the City of Hope Hospital. 21 suggested to the doctor that he prescribe Revlimid for his MM patients who had just In 2007, Relator’s then-manager Shawn Gormish In one ride-along, they called upon Dr. At Gormish’s direction, Relator 22 23 24 25 26 27 28 3 As Harding’s and Rowell’s words plainly show, years before Celgene received approval for treatment of newly diagnosed MM, Celgene already considered Thalomid an MM medication. In a 2003 letter from Sol Barer to Relator, Barer warned of the competition that Thalomid could face for treatment of MM: “[o]ur commercial force will face competition: Velcade will be approved sometime this year for myeloma. While we believe that it will be relegated to a salvage role and doesn’t have the wealth of evidence Thalomid has[,] it is important to remember that we will for the first time have competition.” Thalomid did not receive an MM indication for more than three years after Barer’s letter. Case No. 10-cv-03165 GHK (SSx) 42 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 48 of 141 Page ID #:1320 1 received a bone marrow transplant. During another sales call at the same hospital, 2 Gormish instructed Relator to market Revlimid to Dr. Firoozeh Sahebi (who also 3 worked for Kaiser) for newly diagnosed MM patients. 4 150. Celgene’s highest level management, stationed in New Jersey, also 5 conducted ride-alongs with Relator and other sales representatives. In 2001, Celgene’s 6 Vice President of Sales, Dwight D’Iorio, rode along with Relator. Moreover, Relator is 7 aware that John Jackson, Celgene’s former CEO, performed a ride-along with at least 8 one representative, Jackie Qwon, a representative in the Rockville, Maryland area, in or 9 about 2003 or 2004. 10 d. 11 Celgene’s Misbranding Was Directed By Company Management 12 151. Not only did the company’s management, up to and including CEO John 13 Jackson, observe the misbranding of Thalomid and Revlimid, the decision to market the 14 product was made at the highest levels of the company. 15 152. For example, in its April 8, 2005 business review meeting with senior 16 management the company discussed marketing its products to treat prostate cancer. None 17 of Celgene’s products have ever been approved by the FDA to treat prostate cancer. The 18 company was certainly aware of this. In 2009, Bill Spruill, a Senior Regional Sales 19 Director at Celgene, forwarded a 2005 email string regarding this meeting to Jeff Rowell, 20 by then a national accounts management director. When Rowell noted that the company’s 21 “policy on destroying old information prevents you from still having this,” Spruill 22 responded “[d]ocument retention policy is for losers.” Rowell then told Spruill: 23 25 Think of how smart it is by the company, though. If anyone ever “whistle blows” with old proof either on email or printed, the company can fire them for cause for violating the Records Retention Policy … vs. firing them as “retaliation.” 26 153. In his 2006 evaluation, Company management directed Vice President of 27 Marketing, Mark Alles, “to develop and execute [Revlimid] [marketing] plans for Non 28 5q-MDS, CLL [chronic lymphocytic leukemia] and NHL [non-hodgkin lymphoma].” 24 Case No. 10-cv-03165 GHK (SSx) 43 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 49 of 141 Page ID #:1321 1 The FDA has not approved Revlimid to treat any of these conditions. The instruction to 2 develop a marketing plan for CLL is particularly troublesome. Celgene has long tried to 3 develop evidence that Revlimid is effective to treat leukemia. Its unsuccessful efforts 4 ended in 2013 when the FDA forced it to discontinue a late-stage large study of 5 Revlimid in elderly CLL patients because patients taking the drug had a death rate 6 nearly twice that of patients receiving chemotherapy. 7 5. 8 Celgene Provided Its Sales Force With Marketing Materials Describing Off-Label Uses of Thalomid and Revlimid 9 154. Since 2001, Celgene deluged Relator and other sales representatives with 10 marketing materials concerning a litany of diseases – primarily cancers – for which 11 Thalomid and Revlimid were not FDA approved. Celgene designed these materials 12 specifically to be used in sales calls. 13 155. Soon after Relator completed her formal training at Celgene, the Company 14 provided her and her colleagues with copies of an abstract by Dr. William Figg and 15 others that appeared in the July 2001 issue of Clinical Cancer Research. The objective 16 of the study was to evaluate the response rates (tumor measurements and changes in 17 PSA levels) associated with low-dose and high-dose thalidomide in patients with 18 androgen-independent prostate cancer (“AIPC”). 19 inconclusive. Only 50 patients were enrolled in the low-dose arm; and the high-dose 20 arm was terminated due to the large number of individuals who could not tolerate the 21 dose. There were 560 adverse events reported, ranging from constipation to fatigue, 22 even suicide. About 30% of the patients had a decline of 40% or more in their PSA, but 23 there was no control group. Relator, then a new hire, asked her then manager, Deena 24 Harding, about the study and was told to use it when calling upon doctors who treated 25 prostate cancer. Relator then used this abstract to promote the use of Thalomid for all 26 forms of prostate cancer, not just AIPC. The FDA has never approved Thalomid to treat 27 prostate cancer. The results were, however, 28 Case No. 10-cv-03165 GHK (SSx) 44 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 50 of 141 Page ID #:1322 1 156. Relator’s managers voiced their disapproval when she failed to use this 2 study. For example, in or about 2004, Relator’s then manager Jeff Rowell (“Rowell”) 3 accompanied her during a ride-along that included a visit to Dr. Karo Arzoo in Burbank, 4 California. Rowell observed Relator talking to Dr. Arzoo about Thalomid and prostate 5 cancer. When the conversation ended and Dr. Arzoo returned to an examination room to 6 treat a patient, Rowell angrily confronted Relator in the doctor’s office, demanding that 7 she use the Figg study. They waited until Dr. Arzoo finished with the patient and then 8 Relator – pursuant to her manager’s demand – confronted Dr. Arzoo again and presented 9 the Figg study. 10 157. Upon Revlimid’s launch, Celgene provided Relator with “Revlimid 11 Standard Letters” and a compilation of studies concerning off-label uses for Revlimid. 12 These compilations, as later alleged in this Complaint, include studies concerning 13 Revlimid’s use for the off-label treatment of cancers including off-label combinations 14 and or uses. 15 158. Subsequent to Revlimid’s launch, Celgene provided Relator and other sales 16 representatives information concerning Revlimid’s use in non-indicated forms of MDS. 17 For example, one document Celgene provided to Relator states “Field question/objection 18 addressed: Doesn’t Revlimid only work in those patients with a del5q abnormality” and 19 provides study results that a sales representative can recite to a physician suggesting 20 Revlimid’s purported efficacy in MDS without a del5q deficiency. 21 managers, and its documents routinely referred to “our MDS patients” in an effort to 22 communicate that Revlimid should be used to treat all forms of MDS. Relator routinely 23 probed physicians as to whether they treated general MDS, and then provided this 24 information. Moreover, Relator memorized portions of a study in the New England 25 Journal of Medicine that included partial findings concerning Revlimid’s alleged 26 efficacy in general MDS. Relator provided this information to physicians throughout 27 her employment at Celgene. 28 Case No. 10-cv-03165 GHK (SSx) 45 THIRD AMENDED COMPLAINT Celgene, its Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 51 of 141 Page ID #:1323 1 159. Relator encountered resistance from doctors when she attempted to market 2 Revlimid for use by all MDS patients as directed by the company’s marketing plan. For 3 example, in or about 2006, Relator’s then-manager Shawn Gormish directed her to call 4 upon Dr. Mark Kirschbaum at City of Hope Hospital and to use the probing question “do 5 you have any non 5q deletion MDS patients?” Dr. Kirschbaum responded that he did 6 not currently have any such patients. Nonetheless Relator attempted to market Revlimid 7 for future non 5q deletion MDS patients. At that point, Dr. Kirschbaum answered, 8 “Beverly, that is something I cannot help you with.” Similarly, when Relator suggested 9 to Dr. Mina in 2006 – at the Company’s direction – that he use Revlimid to treat newly 10 diagnosed MM patients, Dr. Mina refused, explaining that the FDA had not approved 11 Revlimid to treat newly diagnosed MM patients. When Relator then suggested that he 12 could use it alone – i.e., not in combination with dexamethasone – to treat newly 13 diagnosed MM patients, he told her that he could not do that as it would be unethical, the 14 patient would not have had any prior treatments. Although these doctors did not respond 15 to Celgene’s misbranding, they were the exception. 16 17 6. Celgene Promoted Off-Label Uses of Thalomid and Revlimid Using Studies and Abstracts That Failed To Provided Scientific Support for the Off-Label Use 18 160. Celgene’s national headquarters provided Relator and other sales personnel 19 with stacks of studies so that she and others could detail physicians on off-label uses. In 20 addition, Celgene routinely made false statements to physicians concerning Thalomid’s 21 and Revlimid’s effectiveness in certain patient populations and withheld important 22 safety information such as the risk of deep vein thrombosis described above. These 23 representations constituted illegal misbranding because they were unsupported by FDA- 24 approved prescribing information. 25 26 161. Celgene provided Relator with abstracts but not the complete studies to present to physicians. In many cases, the underlying studies were seriously flawed. 27 162. For example, shortly after Relator began working for Celgene in 2001, she 28 attempted to market Thalomid for smoldering MM (i.e., early-stage, asymptomatic MM) Case No. 10-cv-03165 GHK (SSx) 46 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 52 of 141 Page ID #:1324 1 at the Ventura, California Hematology and Oncology Clinic. 2 understanding that smoldering MM is never treated, since it is asymptomatic and 3 treatment (which always has side effects) does not affect the course of the disease. 4 Nevertheless, Relator provided physicians at the Ventura facility with a study given to 5 her by Celgene to distribute to doctors in which a total of twelve patients were treated 6 with Thalomid for smoldering MM. The head physician at the Ventura practice, Dr. 7 Kelley, harshly scolded Relator for attempting to market Thalomid based on a woefully 8 inadequate study. It is Relator’s 9 163. In or about 2001, Celgene provided Relator with a binder of materials 10 entitled “Colorectal Cancer.” Curiously, Relator was never trained on colon cancer . 11 When she asked her managers what she was to do with these materials, she was told by 12 Deena Harding that they should be used to promote the use of Thalomid in patients with 13 colorectal cancer. The FDA has never approved Thalomid to treat colon cancer. 14 164. In the binder, Celgene included selling points for Thalomid. For example, 15 (1) a memorandum entitled “Use of Thalidomide in Combination Therapy with 16 Irinotecan in the Treatment of Metastic Colorectal Cancer,” (2) an August 2000 Lancet 17 article by Dr. Rangasnamy Govindarajan and others titled “Effects of Thalomid on the 18 Gastrointestinal Toxic Effects of Irinotecan (CPT-11),” and (3) an August 2000 19 memorandum titled “Thalidomide Reduces Side Effects of Chemotherapy for Colon 20 Cancer,” which presented the purported benefits of using thalidomide in combination 21 with Irinotecan in colorectal cancer patients. In addition to noting a reduced overall 22 incidence of diarrhea in patients given the combination therapy, the 2000 memorandum 23 stated that “[a]necdotally, thalidomide as monotherapy has been noted to be associated 24 with clinical improvement in a few patients with metastic colorectal carcinoma.” 25 However, the memorandum based its conclusion on small, preliminary studies. The 26 Govindarajan study was, for example, a pilot clinical trial involving only nine patients of 27 which eight completed the chemotherapy regimen. One required a dose reduction of 28 thalidomide for somnolence. Of the remaining seven patients, only one had a complete Case No. 10-cv-03165 GHK (SSx) 47 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 53 of 141 Page ID #:1325 1 response. Another patient attained partial remission. Irinotecan is known to have 2 activity in this disease, and the relative contribution of thalidomide is not clear. These 3 results were far short of being sufficiently robust to support Thalomid treatment 4 decisions. Subsequent small studies in 2003, 2006, and 2007 reported a lack of even 5 radiographic response to thalidomide. The Company directed Relator and its sales force 6 to use these materials to promote Thalomid to treat colorectal cancer. Nevertheless, 7 from 2000 to today, there is no evidence that the drug benefits patients with colorectal 8 carcinoma at any stage of disease, either alone or in combination with other agents. 9 165. Celgene’s Medical Affairs department purchased prescribing data which 10 allowed the company to target oncology specialists for off-label sales. Relator and other 11 sales representatives used this information to prepare for their sales calls. For example, 12 if Medical Affairs told Relator that a doctor treated colon cancer, Relator routinely used 13 the materials in the “Colorectal Cancer” binder to market off-label. Medical Affairs 14 assisted the sales force by specifying which abstracts, studies, and reports they should 15 bring. 16 166. Continuing through at least 2011, Celgene provided to Relator and other 17 sales representatives for distribution to physicians, studies concerning non-indicated 18 Revlimid combinations for relapsed MM, such as use with Bortezomib and Melphalan. 19 Additionally, as detailed below, the materials provided to Relator included studies 20 concerning “Monotherapy with Revlimid,” and “Newly Diagnosed [MM] and 21 Revlimid.” 22 167. Celgene provided Relator and her sales colleagues with a “Launch 2006 23 Reprint Cheat Sheet,” that summarized the various abstracts and studies to be used in 24 promoting Thalomid and Revlimid. These studies and abstracts failed, however, to 25 provide legitimate scientific support for the proposed off-label uses. 26 168. For example, Celgene gave its sales representatives an article by Dr. 27 Vincent Rajkumar, which was published in the December 2005 issue of Blood. Celgene 28 directed sales representatives to use the article to “detail” physicians about the use of Case No. 10-cv-03165 GHK (SSx) 48 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 54 of 141 Page ID #:1326 1 Revlimid for newly diagnosed MM. This article, however, was suspect as Dr. Rajkumar 2 received grant support from Celgene. Moreover, there were technical flaws in the 3 underlying study. 4 169. The study purported to compare lenalidomide and dexamethasone to 5 thalidomide and dexamethasone. 6 combination was more effective and less toxic than the latter in treating MM. The 7 article, however, provided no information about the thalidomide group, such as the 8 number of patients, trial period or treatment regimen. Without that information, 9 physicians could not draw reliable conclusions about how lenalidomide compares to 10 thalidomide. Nonetheless, Relator, at Celgene’s direction, provided copies of this study 11 to virtually every doctor she called upon. Dr. Rajkumar suggested that the prior drug 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Case No. 10-cv-03165 GHK (SSx) 49 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 55 of 141 Page ID #:1327 1 170. Celgene also gave its sales representatives copies of what it represented was 2 an article by Michael Wang and other authors, appearing in the December 2008 issue of 3 Blood, for use in persuading physicians that Revlimid could be used in patients 4 previously treated with Thalomid. Yet what appeared to be an article by independent 5 authors was actually an advertisement. In addition, nine of the twelve authors (including 6 four Celgene employees) received financial support from Celgene. Dr. Wang received 7 honoraria from Celgene and research funding for this project. The studies discussed in 8 the article were likewise funded by Celgene. 9 The advertisement appeared to be a legitimate 10 article in a respected journal; only if a reader 11 happened to read a footnote in small type 12 would the reader realize that this was not a 13 peer-reviewed article but an advertisement 14 paid for by Celgene. 15 171. Rather than presenting a new 16 study, 17 analyzes a subset of data obtained from two 18 prior studies conducted by Celgene. 19 authors look at only selected data and results 20 from those prior studies and conclude (from 21 preliminary data in early phase 1 and phase 2 22 trials) that Revlimid alone and in combination 23 with dexamethasone produced a response in patients who had previously received 24 thalidomide. The subgroups analyzed by Wang, however, number as few as ten or 25 fifteen patients – numbers that are too small to provide meaningful results. Indeed, the 26 advertisement noted that the analysis “is a post hoc analysis, performed without pre- 27 specified power calculation or adjustment for multiplicity, and is therefore considered 28 exploratory in nature.” Moreover, the data also demonstrated that a patient who was Case No. 10-cv-03165 GHK (SSx) the Wang 50 THIRD AMENDED COMPLAINT advertisement merely The Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 56 of 141 Page ID #:1328 1 first treated with thalidomide is not likely to do as well on Revlimid as a patient 2 previously treated with another drug. At Celgene’s direction, Relator and her colleagues 3 provided copies of this study to doctors. 4 A complete, full-sized, full-length copy of this advertisement is attached as Exhibit 1. 5 172. Celgene regularly gave its sales professionals materials from ASCO 6 meetings that discussed off-label uses of Revlimid and Thalomid for use in marketing 7 the Company’s drugs. For example, Celgene distributed a document titled “Renal Cell 8 Carcinoma Express Report” from the 38th Annual Meeting of the American Society of 9 Clinical Oncology (ASCO) in 2002 to be used by Relator and others to promote the use 10 of thalidomide for renal cell carcinoma. The material consisted largely of an editorial by 11 Dr. Howard Burris and a summary of presentations by Dr. Robert Amato and Dr. Sandy 12 Srinivas. 13 173. In addition, the material describes two studies that are too small to be 14 meaningful. The first is the initial phase of a study involving only 15 patients treated 15 with thalidomide and IL-2. After 12 weeks eight patients demonstrated a positive 16 response while in seven patients the disease progressed. There was no discussion of 17 adverse events. 18 174. The second study involved only 14 patients, randomized to two groups 19 receiving different doses of thalidomide. All seven patients in the high dose group 20 required dose reduction because of toxicity, and two patients developed DVTs. There 21 was no information on disease responses; the “disease stabilization” rate was 46%, 22 which could be consistent with the natural progress of renal cell carcinoma. 23 Nevertheless, the summary concluded that “thalidomide, either as single-agent or in 24 combination with immunotherapy, often achieves disease stabilization in this otherwise 25 progressive carcinoma.” 26 otherwise incomplete – even taken together, provide no meaningful support for this 27 sweeping conclusion. The studies – small, lacking important information, and 28 Case No. 10-cv-03165 GHK (SSx) 51 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 57 of 141 Page ID #:1329 1 175. Another document Celgene provided to Relator purportedly supporting the 2 use of Thalomid to treat renal cell carcinoma was a study by Dr. Danai Daliani and 3 others, supported by Celgene, published in the August 2002 issue of Lancet. The article 4 reported on a pilot study involving only 20 patients. Only two patients showed any 5 response at all to thalidomide treatment; furthermore, the disease progressed in all 20 6 patients. Dr. Daliani reviewed the results of various small studies (some of which found 7 a response, others of which did not) and concluded that “[t]ogether, our data show some 8 antitumor activity of thalidomide in heavily pretreated patients with [metastatic] RCC 9 and warrant evaluation of the role of thalidomide in RCC patients in controlled, 10 randomized trials.” 11 preliminary, showed that thalidomide had serious toxicities, and were not intended to 12 provide a basis for treating patients, Celgene told Relator and other sales professionals to 13 use the study to promote the use of Thalomid for renal cell carcinoma. Relator, at the 14 Company’s instruction, used this article to market Thalomid to treat renal cell cancer, 15 including to Dr. Mukund Shah in 2005 at the Antelope Valley Cancer Center. The FDA 16 has never approved Thalomid to treat renal cell carcinoma. Even though the studies in the Daliani material were small, 17 176. In short, the articles and studies used by Celgene to market Thalomid and 18 Revlimid off-label lacked sufficient information or indicia of reliability to enable 19 physicians to make objective and informed decisions about prescribing Thalomid or 20 Revlimid. 21 7. 22 23 177. Celgene Trained Its Sales Personnel To “Probe” Physicians In Order to Induce Discussions of Off-Label Thalomid and Revlimid Uses The use of probing questions to prompt a dialogue about the off-label use 24 of Celgene’s drugs was a hallmark of Celgene’s marketing schemes. For example, 25 Celgene directed Relator to ask physicians if they treated patients who suffered from a 26 number of cancers and other diseases so that Relator could segue into Thalomid’s use 27 for these off-label purposes. For instance, Celgene managers directed Relator to ask 28 physicians, “Do you treat any [off-label disease] patients?” If a physician responded Case No. 10-cv-03165 GHK (SSx) 52 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 58 of 141 Page ID #:1330 1 “yes,” Relator was told to highlight studies that purportedly showed strong data 2 supporting Thalomid’s use for the off-label indication. A 2002 Celgene Field Contact 3 Report written by Relator’s then-district sales manager, Deanna Harding, directed 4 Relator to “[i]dentify your goal before walking into the office and establish an 5 appropriate probe question to get you into a discussion.” 6 178. The materials Celgene provided to Relator also described the following 7 “Potential Probes” to use with doctors in promoting the off-label use of Thalomid in 8 combination with Irinotecan in colorectal cancer patients: 9 concerns for treating colorectal pts [patients]?”; “Where do you see Thalomid fitting into 10 your 11 “What are your biggest immunomodulator’s agent with a cytotoxic agent?” treatment regimen?”; and “How do you feel about combining an 12 179. Other training materials suggested questions to pose to doctors in order to 13 prompt a discussion of the use of Thalidomide to treat kidney cancer. For example, 14 Celgene materials stated: 15 17 Dr. Smith, do you have any renal cell patients that have failed IL-2? … Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. … This is why thalidomide is being tried in over 10 clinical trials in the U.S. for renal cell cancer. 18 180. The use of probing questions was a technique not limited to the off-label 19 marketing of Thalomid. For example, an April 27, 2010 email from Andrew Odenwald, 20 a district sales manager, provides questions that sales representatives should ask doctors 21 about Cutaneous T cell lymphoma (“CTCL”), a class of non-Hodgkin's lymphoma, 22 which is a type of cancer of the immune system. The FDA has never approved Revlimid 23 to treat Cutaneous T cell lymphoma. In his email, Odenwald attached “CTCL target 24 lists, CTCL profiling tool[s], and the Cross Functional meeting slides” and said the 25 “critical questions” to ask doctors were: 16 26 27 28 1. How many patients with CTCL are you currently treating? 2. How many new patients with CTCL do you see per year? 3. Are these patients referred by a dermatologist? Case No. 10-cv-03165 GHK (SSx) 53 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 59 of 141 Page ID #:1331 1 8. 2 To Provide Cover For The Company, Celgene Directed Its Sales Force to Secure Off-Label Medical Request Forms 3 181. Celgene used “medical information request forms” to memorialize 4 physician requests for off-label information. A physician’s unsolicited or voluntary 5 request directly to the company for such information generally is not considered 6 evidence of company’s intent to misbrand or off-label market a drug. However, Celgene 7 subverted the “medical information request” process by requiring its sales force to 8 verbally discuss off-label uses of its drugs during visits with physicians and then ask 9 physicians to request materials from Celgene, using “medical information request” 10 forms. 11 physicians, were designed to make it appear that a physician’s request for off-label 12 information from Celgene’s medical services department was entirely voluntary and 13 unsolicited. Celgene started this practice early. At Relator’s second job interview, 14 Deena Harding attributed the FDA’s April 21, 2000 warning letter to a sales 15 representative’s failure to obtain a medical request form. Thus, even before Relator was 16 officially hired, her supervisor-to-be stressed the importance of papering the files by 17 soliciting “unsolicited” request forms. The forms, which were completed by sales representatives and signed by 18 182. Complying with Celgene’s directives, Relator routinely encouraged 19 physicians to order off-label information from Celgene’s medical services department 20 during her sales pitches. If the physician agreed, Relator commonly completed the form 21 for the physician and then asked the physician to sign. Relator sent the signed medical 22 information request forms to Celgene’s headquarters in Summit, New Jersey, which in 23 turn sent the information to the physician. 24 183. Celgene put intense pressure on Relator and other sales personnel to secure 25 as many medical information request forms as possible. Relator’s 2003 Performance 26 Evaluation directed Relator to “obtain a signed Medical Services Request form on each 27 call.” The push to obtain these medical information request forms is illustrated in Chad 28 Saward’s Monthly Activity report for September 2002. He writes, under the heading Case No. 10-cv-03165 GHK (SSx) 54 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 60 of 141 Page ID #:1332 1 “Accomplishments” that he “submitted nearly 30 Med Request Forms” and under 2 “Goals” he wrote “submit a Med. Info Request form for nearly every call.” (In this 3 same monthly activity report he notes, under the heading “message,” that “I discussed 4 colorectal, prostate, renal cell carcinoma, melanoma, MDS and MM. This month I am 5 going back to the basics with a MM focus.” At this time, the FDA had approved 6 Thalomid to treat none of these conditions and only approved it in 2006 for a subset of 7 MM.) 8 184. Relator and other sales representatives who failed to secure sufficient 9 numbers of these medical information request forms were routinely admonished by their 10 superiors while those that obtained large numbers were praised. 11 national sales meeting, a member of Celgene’s marketing department stood and 12 commended the Celgene regional sales force that secured the greatest number of medical 13 information request forms during the previous year. Some of Celgene’s highest level 14 management, including Sol J. Barer (Celgene’s Chief Operating Officer from March 15 1994 to May 1, 2006; Chairman and Chief Executive Officer from May 2006 until June 16 2010; Executive Chairman from June 2010 until December 2010; and Non-Executive 17 Chairman from January 2011 until June 2011), who were present at these meetings, 18 joined in applauding the regional team that secured the most off-label request forms. 19 At almost every 185. If a sales representative’s total submitted medical request forms was low, 20 however, then the representative would be confronted by his/her manager. 21 expected that each sales representative would obtain at least 30 such requests a month. 22 The pressure to obtain these forms was so great that the Relator is aware of at least one 23 person – Chad Saward – that was caught forging doctor’s signatures. Mr. Saward was 24 later promoted by Celgene. It was 25 186. As with Thalomid, Relator’s managers pressured her and other sales 26 representatives to persuade physicians to sign medical request forms for off-label uses of 27 Revlimid. When Revlimid was launched in December 2005, it was approved solely for 28 treatment of transfusion-dependent anemia due to low or intermediate risk MDS Case No. 10-cv-03165 GHK (SSx) 55 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 61 of 141 Page ID #:1333 1 associated with a deletion 5q cytogenic abnormality.4 As previously alleged, deletion 5q 2 cytogenic abnormality is relatively uncommon, as only 20% to 30% of MDS patients 3 suffer from the condition. Nevertheless, Celgene immediately began directing Relator 4 and other sales representatives to market the drug off-label for all types of MDS, 5 including high risk MDS, and MDS without the deletion 5q cytogenic abnormality. As 6 part of this marketing effort, Relator and other sales personnel routinely secured these 7 medical request forms for general MDS. 8 187. Celgene’s directive to circumvent the “medical information request” 9 process was intended to further the Company’s goal of unlawfully increasing its sales of 10 Thalomid and Revlimid, as well as to provide needed but superficial “cover” should 11 regulators learn that the Company had unlawfully distributed materials outside the 12 drugs’ labeling. 13 9. 14 Celgene Directed Its Sales Force To “Push The Dose” With Thalomid 15 188. Thalomid is more expensive as the dose increases. Accordingly, Celgene 16 directed sales representatives, including Relator, to encourage physicians to prescribe 17 high doses of Thalomid, and sales representatives received larger bonuses for higher 18 dosages. Celgene’s marketing strategy focused on those diseases for which patients in 19 studies were given very high doses of Thalomid. For example, Celgene’s managers 20 directed Relator to target physicians who treated renal cell (i.e., kidney) cancer, because 21 there existed published studies where renal cell cancer patients were treated with up to 22 1200mg of Thalomid per day (1200mg is a very high dose of Thalomid). Allison Tozer, 23 a Medical Information Specialist at Celgene’s headquarters in New Jersey, provided 24 Relator with stacks of these and other studies to distribute directly to physicians. 25 Celgene directed Relator to detail physicians concerning these studies and related off- 26 label uses of Thalomid. 27 28 4 To this day, Revlimid is still not FDA-approved for any other type of MDS. Case No. 10-cv-03165 GHK (SSx) 56 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 62 of 141 Page ID #:1334 1 189. Relator also targeted physicians that treated glioblastoma (i.e., brain cancer) 2 patients, because there were studies that used extremely high Thalomid dosage levels in 3 treatment. In an effort to target these physicians, Celgene’s national sales operations 4 provided Relator and other sales representatives with lists of physicians in their areas 5 that prescribed Temodar, a popular brain cancer medication. Celgene directed its sales 6 representatives to persuade these doctors to use Thalomid to treat brain cancers. 7 190. Notwithstanding Celgene’s efforts to target brain and kidney cancer 8 specialists, Relator and other representatives often encountered resistance from 9 physicians related to “pushing the dose,” because many patients cannot tolerate high 10 doses of Thalomid. Elevated doses can cause VTE, peripheral neuropathy, neutropenia, 11 and constipation. 12 191. In May 2002, for example, Dr. Devitt objected to Chad Saward’s efforts to 13 push the dose. According to Saward’s notes in his May 2002 Monthly Activity report, 14 Dr. Devitt had “10 MM and 10 MDS patients” but “she was not aware of any evidence 15 to support increasing the dose [and therefore Saward] share[d] the Barlogie Benchmark 16 analysis” with Dr. Devitt. He was referring to “Extended Survival in Advanced and 17 Refractory Multiple Myeloma after Single-Agent Thalidomide: Identification of 18 Prognostic Factors in a Phase 2 Study of 169 Patients,” authored by Dr. Bart Barlogie 19 and others in the 2001 edition of Blood. At this time, Thalomid was not approved by the 20 FDA to treat any form of MM or MDS. (Saward’s report for May 2002 also stated that 21 his “message has been MM and MDS”). Later that year, in his December Monthly 22 Activity report, Saward continued to describe his efforts to push the dose. Under goals, 23 he wrote “increase my average dose in December vs November.” 24 10. 25 Celgene Provided Relator and Other Sales Personnel With “Training” Materials Describing Off-Label Uses, Most of Which Failed to Provide Scientific Support For the Off-Label Use 26 192. Celgene routinely provided Relator and other sales personnel with materials 27 purportedly for “training” and/or “education” that provided detailed information 28 regarding off-label uses of Thalomid or Revlimid. Relator’s managers instructed her, Case No. 10-cv-03165 GHK (SSx) 57 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 63 of 141 Page ID #:1335 1 and other sales representatives, to use these materials despite their designation, to market 2 to physicians. 3 193. For example, in 2001 Celgene provided Relator and other sales personnel 4 with “training” materials to be used to promote the use of Thalomid in patients with 5 renal cell (kidney) cancer. These materials, purportedly authored or assembled by Hank 6 Schwarz, a Clinical Science Liaison, stated that: 7 8 9 10 11 12 Thalomid appears to have anti-angiogenic benefits. Since kidney cancer is very vascular and attracts blood vessels, anti-angiogenic therapy is the next frontier in the battle against kidney cancer. 194. The training materials provided by Celgene to its sales force provided the following summaries of ongoing trials about Thalomid: 17 Despite employing a low dose of thalidomide, we observed encouraging responses in patients with renal cell carcinoma. In 18 patients treated for renal carcinoma, three showed partial responses to thalidomide and 13 showed stable disease, three of them for more than 3 months. * * * Our findings suggest that thalidomide may be useful in the management of advanced renal cell carcinoma and possibly of symptomatic benefit in other solid malignancies. 18 195. There is no clear published evidence of clinical benefits of thalidomide in 19 renal cell carcinoma at any stage of disease, either alone or in combination with other 20 therapies. Early studies used duration of stable disease as an endpoint. This endpoint is 21 not meaningful in a disease which can have long indolent periods. A negative study in 22 2006 led authors to conclude that the risks of thalidomide outweigh potential benefits, 23 and publications subsequently recommended against use of thalidomide in this disease. 13 14 15 16 24 196. Relator was never trained on renal cell cancer. When she asked what she 25 was to do with these materials, she was told by her managers to give the studies to 26 doctors, which she – like other sales representatives – did. 27 197. The below chart summarizes some of the studies that the company provided 28 Relator, all of which related to one or more uses of Thalomid or Revlimid that were not Case No. 10-cv-03165 GHK (SSx) 58 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 64 of 141 Page ID #:1336 1 approved by the FDA at the time the study or abstract was written and distributed. In 2 some cases, Celgene sent the Relator dozens of copies of studies stamped “do not 3 distribute.” 4 5 Study or Abstract Title 6 Myelosuppresion Associated With Novel Therapies in Patients With Multiple Myeloma: Consensus Statement of the IMF Nurse Leadership Board 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Study or Abstract Author(s) Miceli, et al. Publication Thromboembolic Events Associated With Novel Therapies in Patients With Multiple Myeloma: Consensus Statement of the IMF Nurse Leadership Board Rome, et al. Clinical Journal of Oncology Nursing. June 2008, Supplement to 12(3) Peripheral Neuropathy Associated With Novel Therapies in Patients With Multiple Myeloma: Consensus Statement of the IMF Nurse Leadership Board Tariman, et al. Clinical Journal of Oncology Nursing. June 2008, Supplement to 12(3) Gastrointestinal Side Effects Associated With Novel Therapies in Patients With Multiple Myeloma: Consensus Statement of the IMF Nurse Leadership Board Smith, et al. Clinical Journal of Oncology Nursing. June 2008, Supplement to 12(3) Steroid-Associated Side Effects in Patients With Multiple Myeloma: Consensus Statement of the IMF Nurse Leadership Board Faiman, et al. Clinical Journal of Oncology Nursing. June 2008, Supplement to 12(3) Stem Cell Mobilization with Cyclophosphamide Overcomes the Suppressive Effect of Lenalidomide Therapy on Stem Cell Collection in Multiple Myeloma Mark, et al. Biology of Blood and Marrow Transplantation. 2008; 14(7) 28 Case No. 10-cv-03165 GHK (SSx) 59 THIRD AMENDED COMPLAINT Clinical Journal of Oncology Nursing. June 2008, Supplement to 12(3) Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 65 of 141 Page ID #:1337 1 Study or Abstract Author(s) List, et al. Publication Relationship of Treatment-Related Cytopenias and Response to Lenalidomide in Patients With Lower-Risk Myelodysplastic Syndromes Sekeres, et al. Journal of Clinical Oncology. 2008; 26(36) Lenalidomide plus Dexamethasone for Relapsed or Refractory Multiple Myeloma Dimopoulous, et al. New England Journal of Medicine. 2007; 357(21) Wang, et al. Blood. 2008; 112(12) 15 Lenalidomide plus Dexamethasone Is More Effective than Dexamethasone Alone in Patients with Relapsed or Refractory Multiple Myeloma Regardless of Prior Thalidomide Exposure 16 Multiple Myeloma Kyle, et al. New England Journal of Medicine. 2004; 351(18) Advances in Oral Therapy for Multiple Myeloma Morgan, et al. Lancet Oncology. 2006; 7 Advances in Oral Therapy in the Treatment of Multiple Myeloma Doss Clinical Journal of Oncology Nursing. 2006; 10(4) 2 3 4 5 6 7 8 9 10 11 12 13 14 Study or Abstract Title Lenalidomide: Targeted Anemia Therapy for Myelodysplastic Syndromes 17 18 19 20 21 22 23 24 25 26 27 Cavo, et al. Superiority of Thalidomide and Dexamethasone Over VincristineDoxorubicin-Dexamethasone (VAD) as Primary Therapy in Preparation for Autologous Transplantation for Multiple Myeloma 28 Case No. 10-cv-03165 GHK (SSx) 60 THIRD AMENDED COMPLAINT Cancer Control. 2006; 13 (Supplement) Blood. 2005; 106(1) Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 66 of 141 Page ID #:1338 1 2 3 4 5 6 7 8 9 10 11 Study or Abstract Title Phase III Clinical Trial of Thalidomide Plus Dexamethasone Compared With Dexamethasone Alone in Newly Diagnosed Multiple Myeloma: A Clinical Trial Coordinated by the Eastern Cooperative Oncology Group Study or Abstract Author(s) Rajkumar, et al. Publication Journal of Clinical Oncology. 2006; 24(3) Palumbo, et al. Oral Melphalan and Prednisone Chemotherapy Plus Thalidomide Compared with Melphalan and Prednisone Alone in Elderly Patients With Multiple Myeloma: Randomized Controlled Trial The Lancet. 2006; 367 Maintenance Therapy with Thalidomide Improves Survival in Patients with Multiple Myeloma Attal, et al. Blood. 2006; 108(10) Combination Therapy with Lenalidomide plus Dexamethasone (Rev/Dex) for Newly Diagnosed Myeloma Rajkumar, et al. Blood. 2005;106(13) Lenalidomide and Pegylated Liposomal Doxorubicin-Based Chemotherapy for Relapsed or Refractory Multiple Myeloma: Safety and Efficacy Baz, et al. Annals of Oncology. September 2006 A Randomized Phase 2 Study of Lenalidomide Therapy for Patients with Relapsed or Relapsed and Refractory Multiple Myeloma Richardson, et al. Blood. 2006; 108(10) 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Case No. 10-cv-03165 GHK (SSx) 61 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 67 of 141 Page ID #:1339 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Study or Abstract Title Management of Thalidomide Toxicity Publication Ghobrial, et al. Prevention of Pulmonary Embolism and Deep Vein Thrombosis with Low Dose Aspirin: Pulmonary Embolism Prevention (PEP) Trial Study or Abstract Author(s) Rodgers The Journal of Supportive Oncology. 2003; 1(3) British Journal of Haernatology. 2004; 126(5) Zangari, et al. Deep Vein Thrombosis in Patients with Multiple Myeloma Treated with Thalidomide and Chemotherapy: Effects of Prophylactic and Therapeutic Anticoagulation The Lancet. 2000; 355 The Role of Aspirin in the Prevention of Thrombotic Complications of Thalidomide and Anthracycline-Based Chemotherapy for Multiple Myeloma Baz, et al. Mayo Clinic Proceedings. 2005; 80(12) Thromboembolism risk reduction in multiple myeloma patients treated with immunomodulatory drug combinations Hussein Thrombosis & Hemostasis. 2006; 95(6) A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma Richardson, et al. Bortezomib Therapy Alone and in Combination with Dexamethasone for Previously Untreated Symptomatic Multiple Myeloma Jagannath, et al. New England Journal of Medicine. 2003; 348 British Journal of Haematology. 2005; 129(6) PAD Combination Therapy (PS341/bortezomib, doxorubicin and dexmethasone) for Previously Untreated Patients with Multiple Myeloma Oakervee, et al. 28 Case No. 10-cv-03165 GHK (SSx) 62 THIRD AMENDED COMPLAINT British Journal of Haematology. 2005; 129(6) Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 68 of 141 Page ID #:1340 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Study or Abstract Title Study or Abstract Author(s) Richardson, et al. Publication Clinical Factors Predictive of Outcome with Bortezomib in Patients with Relapsed, Refractory Multiple Myeloma Richardson, et al. Blood. 2005; 106(9) Bortezomib plus Dexamethasone as Induction Treatment Prior to Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma: Results of an IFM Phase II Study Harousseau, et al. Haematologica. 2006; 91(11) Thalidomide - A Revival Story Raje, et al. New England Journal of Medicine. 1999; 341(21) Antitumor Activity of Thalidomide in Refractory Multiple Myeloma Singhal, et al. New England Journal of Medicine. 1999; 341(21) Extended Survival in Advanced and Refractory Multiple Myeloma after Single-Agent Thalidomide: Identification of Prognostic Factors in a Phase 2 Study of 169 Patients Barlogie, et al. Blood. 2001; 98(2) First-line Therapy with Thalidomide and Dexamethasone in Preparation for Autologous Stem Cell Transplantation for Multiple Myeloma. Cavo, et al. Haematologica. 2004; 89(7) Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma 15 New England Journal of Medicine. 2005; 352(24) 16 17 18 19 20 21 22 23 24 25 26 27 28 Case No. 10-cv-03165 GHK (SSx) 63 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 69 of 141 Page ID #:1341 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Study or Abstract Title Study or Abstract Author(s) Daliani, et al. Publication Temozolomide Plus Thalidomide in Patients With Advanced Melanoma: Results of a Dose-Finding Trial Hwu, et al. Journal of Clinical Oncology. 2002; 20(11) Thalidomide for the Treatment of patients with MDS Strupp, et al. Leukemia. 2002; 16(1) A Pilot Study of Thalidomide in Patients with Progressive Metastatic Renal Cell Carcinoma A Randomized Phase II Trial of Figg, et al. Thalidomide, an Angiogenesis Inhibitor, in Patients with Androgenindependent Prostate Cancer Clinical Cancer Research. 2001; 7. Thalidomide Produces Transfusion Independence in Long-standing Refractory Anemias of Patients with Myelodisplastic Syndromes Raza, et al. Blood. 2001; 98(4) Colorectal and Anal Cancers Pazdur, et al. Cancer Management: A Multidisciplinary Approach 18 19 20 21 Renal Cell Carcinoma Express Report: Encouraging Preliminary Results from Thalidomide in Renal Cell Carcinoma 38th Annual Meeting of the American Society of Clinical Oncology (ASCO) May 16-21, 2002 22 23 Cancer. 2002; 95(4) Compendia-Based Drug Bulletin N/A 24 25 26 27 28 Case No. 10-cv-03165 GHK (SSx) 64 THIRD AMENDED COMPLAINT Compendia-Based Drug Bulletin. 2006; 15(2) Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 70 of 141 Page ID #:1342 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Study or Abstract Title Study or Abstract Author(s) Hideshima, et al. Publication Apoptotic Signaling Induced by Immunomodulatory Thalidomide Analogs in Human Multiple Myeloma Cells: Therapeutic Implications Mitsiades, et al. Blood. 2002; 99(12) Thalidomide Selectively Modulates the Density of Cell Surface Molecules Involved in the Adhesion Cascade Geitz, et al. Immunopharmacology . 1996; 31. Adherence of Multiple Myeloma Cells to Bone Marrow Stromal Cells Upregulates Vascular Endothelial Growth Factor Secretion: Therapeutic Applications Gupta, et al. Leukemia. 2001; 15. Immunomodulatory Analogs of Thalidomide Inhibit Growth of Hs Sultan Cells and Angiogenesis in Vivo Lentzsch, et al. Leukemia. 2003; 17. Thalidomide and Immunomodulatory Derivatives Augment Natural Killer Cell Cytoxicity in Multiple Myeloma Davies, et al. Blood. 2001; 98(1) Thalidomide and its Analogs Overcome Drug Resistance of Human Multiple Myeloma Cells to Conventional Therapy Initial Stages of Tumor Cell-Induced Li, et al. Angiogenesis: Evaluation Via Skin Window Chambers in Rodent Models 27 28 Case No. 10-cv-03165 GHK (SSx) 65 THIRD AMENDED COMPLAINT Blood. 2000; 96(8) Journal of the National Cancer Institute. 2000; 92(2) Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 71 of 141 Page ID #:1343 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Study or Abstract Title Clinical Application of Antiangiogenic Therapy: Microvessel Density, What It Does and Doesn't Tell Us Study or Abstract Author(s) Hlatky, et al. Impact of Lenalidomide Therapy on Kumar, et al. Stem Cell Mobilization and Engraftment Post-peripheral Blood Stem Cell Transplantation in Patients with Newly Diagnosed Myeloma Publication Journal of the National Cancer Institute. 2002; 94(12) Leukemia. 2007; 21 Melphalan and Prednisone plus Thalidomide versus Melphalan and Prednisone Alone or Reducedintensity Autologous Stem Cell Transplantation in Elderly Patients with Multiple Myeloma (IFM 9906): a Randomized Trial Facon, et al. Lancet. 2007; 370 Lenalidomide plus Dexamethasone (Rev/Dex) in Newly Diagnosed Myeloma: Response to Therapy, Time to Progression, and Survival Lacy, et al. Blood. 2006; 108(11) Oral Revlimid plus Melphalan and Prednisone (R-MP) for Newly Diagnosed Multiple Myeloma: Results of a Multicenter Phase I/II Study Palumbo, et al. Blood. 2006; 108(11) Melphalan (M), prednisone (P) and lenalidomide ® combination (MPR) for newly diagnosed multiple myeloma patients who are not candidates for stem cell transplantation Roy, et al. Blood. 2006; 108(11) 27 28 Case No. 10-cv-03165 GHK (SSx) 66 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 72 of 141 Page ID #:1344 1 2 3 4 5 6 7 8 9 10 11 Study or Abstract Title Lenalidomide plus High-dose Dexamethasone Provides Improved Overall Survival Compared to HighDose Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma (MM): Results of 2 Phase II Studies (MM-009, MM-010) and Subgroup Analysis of Patients with Impaired Renal Function Study or Abstract Author(s) Weber, et al. Publication Blood. 2006; 108(11) Lenalidomide in Combination with Stadtmauer, et al. Dexamethasone is more Effective than Dexamethasone at First Relapse in Relapsed Multiple Myeloma Blood. 2006; 108(11) Chanan-Khan, et Lenalidomide (L) in Combination with Dexamethasone (D) al. Significantly Improves Time to Progression (TTP) in Non-stem Cell Transplant Patients (pts) with Relapsed or Refractory (rel/ref) in Multiple Myeloma (MM): Analysis from MM-009 and MM-010 Randomized Phase III Clinical Trials Blood. 2006; 108(11) 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Lenalidomide overcomes poor prognosis conferred by deletion of chromosome 13 and t(4;14) in multiple myeloma: MM016 trial Bahlis, et al. Blood. 2006; 108(11) Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group Rajkumar, et al. Abstract 28 Case No. 10-cv-03165 GHK (SSx) 67 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 73 of 141 Page ID #:1345 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Study or Abstract Title Study or Abstract Author(s) Chen, et al. Abstract A Randomized Phase 2 study of Lenalidomide Therapy for Patients with Relapsed or Relapsed and Refractory Multiple Myeloma Richardson, et al. Blood. 2006; 108(10) Doxil (D), vincristine (V), Reduced Frequency Dexamethasone (d) and Revlimid DVd-R) a Phase I/II Trial in Advanced Relapsed/refractory Multiple Myeloma (Rmm) Patients Hussein, et al. Abstract Symposium on Oncology Practice: Hematological Malignancies - The Myelodysplastic Syndromes: Diagnosis and Treatment Steensma, et al. Mayo Clinic Proceedings. 2006; 81(1) A phase II trial of lenalidomide for patients with AL amyloidosis Sanchorawala, et al. Abstract Skin reactions associated with oral Revlimid (lenalidomide) in AL amyloidosis (ALA); Patient teaching encouraging prompt reporting, and clinical assessment and management of skin reactions can impact patient outcomes Finn, et al. Oncology Nursing Forum. 2006; 33(2) Lenalidomide has activity in a phase II trial in patients with primary systemic amyloidosis Dispenzieri, et al. Abstract Reversal of myelofibrosis in a patient Besa, et al. Abstract Pharmacokinetics of lenalidomide in subjects with various degrees of renal function Publication 25 26 27 28 Case No. 10-cv-03165 GHK (SSx) 68 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 74 of 141 Page ID #:1346 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Study or Abstract Title A phase I trial of CC-5013, a potent thalidomide analog, in patients with recurrent high-grade gliomas and other refractory CNS malignancies Study or Abstract Author(s) Fine, et al. Miller, et al. Lenalidomide (L) induces high response rates with molecular remission in patients (pts) with relapsed (rel) or refractory (ref) chronic lymphocytic leukemia (CLL) Publication Abstract Abstract Antileukemic activity of lenalidomide (L) (Revlimid) in patients (pts) with relapsed (REL) or refractory (REF) chronic lymphocytic leukemia (CLL) Chanan-Khan, et al. Abstract Prednisone (P) Prophylaxis Decreases Incidence and Severity of Lenalidomide (L) Induced Flare Reaction (flr) in Patients with Relapse (rel) or Refractory (ref) Chronic Lymphocytic Leukemia Musial, et al. Abstract Clinical Characteristics and Management Strategy of RevlimidInduced Tumor Flare Reaction in Patients with CLL Results of Phase II Study of Lenalidomide (L) (Revlimid) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) Miller, et al. Oncology Nursing Forum. 2006; 33(2) Chanan-Khan, et al. Blood. 2005; 106(11) Lenalidomide in Patients with Cutaneous T-cell Lymphoma. Preliminary Data of Phase II Trial Querfeld, et al. Abstract 28 Case No. 10-cv-03165 GHK (SSx) 69 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 75 of 141 Page ID #:1347 1 2 3 4 5 6 7 8 9 10 11 Study or Abstract Title Study or Abstract Author(s) Results of Phase I Study of CO-5013 Zangari, et al. for the Treatment of Multiple Myeloma (MM) Patients who Relapse after High-Dose Chemotherapy (HDCT) Publication Abstract A Multi-Center, Randomized, Phase 2 Study to Evaluate the Efficacy and Safety of 2 CDC-5013 Dose Regimens When Used Alone or in Combination with Dexamethasone (Dex) for the Treatment of Relapsed or Refractory Multiple Myeloma (MM) Richardson, et al. Abstract Revlimid 25 mg (REV 25) x 20 Versus 50 mg (REV 50) x 10 g 28 Days with Bridging of 5 mg x 10 Versus 10 mg x 5 as Post-Transplant Salvage Therapy for Multiple Myeloma (MM) Zangari, et al. Abstract A Multicenter, Single-arm, Openlabel Study to Evaluate the Efficacy and Safety of Single-agent Lenalidomide in Patients with Relapsed and Refractory Multiple Myeloma; Preliminary Results Richardson, et al. Abstract Doxil (D), Vincristine (V), Reduced Frequency Dexamethasone (d) and Revlimid [DVd-R]) Results in a High Response Rate in Patients with Refractory Multiple Myeloma (RMM) Baz, et al. Blood. 2005; 106(11) 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Case No. 10-cv-03165 GHK (SSx) 70 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 76 of 141 Page ID #:1348 1 2 3 4 5 6 7 8 9 10 11 12 13 Study or Abstract Title Study or Abstract Author(s) Richardson, et al. Publication Evaluating Oral Lenalidomide (Revlimid) and Dexamethasone versus Placebo and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma Dimopoulous, et al. Abstract Study of Lenalidomide plus Dexamethasone versus Dexamethasone Alone in Relapsed or Refractory Multiple Myeloma (MM): Results of a Phase 3 Study (MM-010) Dimopoulous, et al. Abstract A Multicenter Phase I/II Trial Evaluating the Safety and Efficacy of Lenalidomide (Revlimid, CC5013) in Combination with Doxorubicin and Dexamethasone (RAD) in Patients with Relapsed or Refractory Multiple Myeloma Gerecke, et al. Blood. 2005; 106(11) Lenalidomide (Revlimid), in Combination with Cyclophosphamide and Dexamethasone (CRD) Is an Effective Regimen for Heavily PreTreated Myeloma Patients. Davies, et al. Abstract A Phase 1 Trial of Lenalidomide (REVLIMID) with Bortezomil (VELCADE) in Relapsed and Refractory Multiple Myeloma Blood. 2005; 106(11) 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Niesvizky, et al. BiRD (Biaxin/Revlimid/Dexamethasone) Combination Therapy (Rx) Results in High Complete Remissions (CR) and Overall Responses in Myeloma (MM) with Poor Prognostic Features Case No. 10-cv-03165 GHK (SSx) 71 THIRD AMENDED COMPLAINT Blood. 2005; 106(11) Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 77 of 141 Page ID #:1349 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Study or Abstract Title Study or Abstract Author(s) Niesvizky, et al. Publication Oral Lenalidomide plus Melphalan and Prednisone (R-MP) for Newly Diagnosed Multiple Myeloma Palumbo, et al. Abstract High Incidence of Thrombotic Events Observed in Patients Receiving Lenalidomide (L) + Dexamethasone (D) (LD) as Firstline Therapy for Multiple Myeloma (MM) without Aspirin (ASA) Prophylaxis Zonder, et al. Abstract Weber, et al. Lenalidomide plus High-dose Dexamethasone Provides Improved Overall Survival Compared to Highdose Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma (MM): Results of a North American Phase III Study (MM-009) Abstract Clarithromycin, Lenalidomide and Dexamethasone Combination Therapy as Primary Treatment of Multiple Myeloma Abstract Lenalidomide (Revlimid) in Combination with Dexamethasone (DEX) is more Effective than DEX alone in Patients with Relapsed or Refractory Multiple Myeloma Who Have Received Prior Thalidomide Therapy Blade, et al. Abstract Increased Risk of Thrombosis with Lenalidomide in Combination with Dexamethasone and Erythropoietin Niesvizky, et al. Abstract 27 28 Case No. 10-cv-03165 GHK (SSx) 72 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 78 of 141 Page ID #:1350 1 2 3 4 5 6 7 8 9 10 11 Study or Abstract Title Study or Abstract Author(s) Wang, et al. Publication Lenalidomide (Len) in Combination with Dexamethasone (Dex) is more Effective than Dex Alone at first Relapse and Provides Better Outcomes when Used Early Rather than as Later Salvage Therapy in Relapsed Multiple Myeloma (MM) Stadtmauer, et al. Abstract Lenalidomide (Revlimid) Combination with Dexamethasone (DEX) is more Effective than DEX alone in Patients with Relapsed or Refractory Multiple Myeloma and Independent of Number of Previous Treatments Dimopoulous, et al. Abstract Comparison of Lenalidomide in Combination with Dexamethasone to Dexamethasone Alone in Patients Who Have Received Prior Thalidomide in Relapsed or Refractory Multiple Myeloma Abstract 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 List, et al. Results of the MDS-002 and -003 International Phase II studies Evaluating Lenalidomide (CC-5013; Revlimid) in the Treatment of Transfusion-dependent (TD) Patients with Myelodysplastic Syndrome (MDS) Lenalidomide (CC-5013; Revlimid)induced Red Blood Cell (RBC) Transfusion-independence (TI) Response in Low-/Int 1-risk Patients with Myelodysplastic Syndromes (MDS): Results of the Multicenter MDS 002 Study Case No. 10-cv-03165 GHK (SSx) Razal, et al. 73 THIRD AMENDED COMPLAINT Abstract Abstract Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 79 of 141 Page ID #:1351 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Study or Abstract Title Study or Abstract Author(s) Phase II Study of Lenalidomide (CC- Verstovsek, et al. 5013) for Patients with Myelofibrosis Publication Reversal of Myelofibrosis in a Besa, et al. Patient with Low-risk Myelofibrostic Syndrome on Revlimid Therapy Blood. 2005; 106(11) Preliminary Results from Two-phase Wiernik, et al. II Studies of Lenalidomide Monotherapy in Relapsed/refractory Non-Hodgkin’s' Lymphoma Abstract Preliminary Results from a Phase II Wiernik, et al. Study of Lenalidomide Monotherapy in Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma Abstract Phase II Study of CC-5013 in Patients (pts) with Metastatic Renal Cell Cancer (MRCC) Rawat, et al. Abstract Phase II Study of CC-6013 in Patients with Renal Cell Cancer Amato, et al. Abstract Tolerability of the Novel Oral Thalidomide Analog CC-6013 Demonstrating Extensive Immune Activation and Clinical Response Sharma, et al. Abstract Doxil (D), Vincristine (V), Reduced Frequency Dexamethasone (d) and Revlimid ( R ) (DVd-R) Rests in a High Response Rate in Patients with Refractory Multiple Myeloma (RMM) Baz, et al. Blood. 2005; 106(11) 28 Case No. 10-cv-03165 GHK (SSx) 74 THIRD AMENDED COMPLAINT Abstract Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 80 of 141 Page ID #:1352 1 2 3 4 5 6 7 8 9 10 11 Study or Abstract Title Study or Abstract Author(s) Niesvizky, et al. Publication Clarithromyein, Lenalidomide and Dexamethasone Combination Therapy as Primary Treatment of Multiple Myeloma Niesvizky, et al. Abstract Lenalidomide in the Context of Complex Karyotype or Interrupted Treatment: Case Reviews of Del(5q)MDS Patients with Unexpected Responses Giagounidis, et al. Annals of Hematology. 2007; 86 BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) Combination Therapy Results in High Complete- and Overallresponse Rates in Treatment-naïve Symptomatic Multiple Myeloma Niesvizky, et al. Blood. 2008; 111(3) A Prognostic Score for Patients with Lower Risk Myelodysplastic Syndrome Garcia-Manero, et al. Leukemia. 2007; 21 Treatment of Newly Diagnosed Multiple Myeloma Based on Mayo Stratification of Myeloma and RiskAdapted Therapy (mSMART): Consensus Statement Dispenzieri, et al. Increased Risk of Thrombosis with Lenalidomide in Combination with Dexamethasone and Erythropoletin Abstract 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Case No. 10-cv-03165 GHK (SSx) 75 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 81 of 141 Page ID #:1353 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Study or Abstract Title Randomized Trial of Lenalidomide plus High-dose Dexamethasone versus Lenalidomide plus Low-dose Dexamethasone in Newly Diagnosed Myeloma (E4A03), a Trial Coordinated by the Eastern Cooperative Oncology Group: Analysis of Response, Survival, and Outcome with Stem Cell Transplantation Study or Abstract Author(s) Rajkumar, et al. Publication Abstract A Randomized Southwest Oncology Zonder, et al. Group Study Comparing Dexamethasone (D) to Lenalidomide + Dexamethasone (LD) as Treatment of Newly-diagnosed Multiple Myeloma (NDMM): Impact of Cytogenetic Abnormalities on Efficacy of LD, and Updated Study Results Abstract Final Analysis of MM-014: Singleagent Lenalidomide in Patients with Relapsed or Refractory Multiple Myeloma Abstract 16 17 18 19 20 21 22 23 24 25 Hussein, et al. Palumbo, et al. Bortezomib, Pegylated-lyposomaldoxorubicin and Dexamethasone (PAD) as Induction Therapy Prior to Reduced Intensity Autologous Stem Cell Transplant (ASCT) Followed by Lenalidomide and Prednisone (LP) as Consolidation and Lenalidomide Alone as Maintenance 26 27 28 Case No. 10-cv-03165 GHK (SSx) 76 THIRD AMENDED COMPLAINT Abstract Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 82 of 141 Page ID #:1354 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Study or Abstract Title Study or Abstract Author(s) Safety and Efficacy of Lenalidomide Richardson, et al. (Len), Bortezomib (Bz), and Dexamethasone (Dex) in Patients (pts) with Newly Diagnosed Multiple Myeloma (MM): A Phase I/II Study Publication Abstract Prolonged Overall Survival with Lenalidomide Plus Dexamethasone Compared with Dexamethasone Alone in Patients with Relapsed or Refractory Multiple Myeloma. Session Type: Oral Session Weber, et al. Blood. 2007; 110(11) Clinical Management of Myelodysplastic Syndromes With Interstitial Deletion of Chromosome 5q Nimer Journal of Clinical Oncology. 2006; 24(18) Dimopoulous, et Long-term Follow-up on Overall Survival from the MM-009 and MM- al. 010 Phase III Trials of Lenalidomide plus Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma Leukemia. 2009; 23 Raza, et al. Phase II Study of Lenalidomide in Transfusion - Dependent, Low-and Intermediate-1 Risk Myelodysplastic Syndrome with Karyotypes Other Than Deletion 5q Blood. 2008; 1(111) Lenalidomide in the Myelodysplastic List, et al. Syndrome with Chromosome 5q Deletion New England Journal of Medicine. 2006; 355 26 27 28 Case No. 10-cv-03165 GHK (SSx) 77 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 83 of 141 Page ID #:1355 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Study or Abstract Title Safety and Efficacy of Single-agent Lenalidomide in Patients with Relapsed and Refractory Multiple Myeloma [abstract] Safety and Efficacy of Single-agent Lenalidomide in Patients with Relapsed and Refractory Multiple Myeloma Study or Abstract Author(s) Richardson, et al. Publication Richardson, et al. Blood. 2009; 114(4) Most Common Medical Information Requests (Listed in order by disease state) Materials that are Allowed to Be Given Out at Congresses and Conventions 12/4 N/A N/A IS Educational Information Summary - June 2003 Managing Patients With Low-Risk MDS Sekeres, et al. Clinical Roundtable Monograph. July 2006 Treatment Options for Low-Risk MDS Sekeres Clinical Advances in Hematology & Oncology. 2006; 4(7), Supp. 16 Treating Patients with Low-Risk MDS: Nurses' Perspective Cosgrove, et al. Clinical Advances in Hematology & Oncology. 2006; 4(7), Supp. 16 Combination Therapy with CC-5013 (lenalidomide; Revlimid) plus Dexamethasone (Rev/Dex) for Newly Diagnosed Myeloma (MM) Rajkumar, et al. 20 21 22 23 24 25 26 27 Blood. 2009; 114(4) 28 Case No. 10-cv-03165 GHK (SSx) 78 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 84 of 141 Page ID #:1356 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Study or Abstract Title Study or Abstract Author(s) Cazzola, et al. Publication Impact of Risk Stratification on Outcome among Patients with Multiple Myeloma Receiving Initial Therapy with Lenalidomide and Dexamethasone Kapoor, et al. Blood. 2009; 114(3) The Efficacy of Thalidomide and Irinotecan in Metastatic Colorectal Carcinoma (phase II study) Govindarajan, et al. Abstract Clinical and Pharmacokinetic Study of Thalidomide in Patients with Advanced Refractory Metastatic Colorectal Cancer Dal Lago, et al. Abstract Effect of Thalidomide on Gastrointestinal Toxic Effects of Irinotecan Govindarajan, et al. Abstract Myelodysplastic Syndromes Coping with Ineffective Hemtopoiesis New England Journal of Medicine. 2005; 352 (6) Irinotecan/Thalidomide in Metastatic Govindarajan Colorectal Cancer Oncology. 2002; Supplement Thalidomide Alone and in Combination for Previously Untreated Myeloma Weber, et al. Abstract Hypothyroidism in Patients with Multiple Myeloma Following Treatment with Thalidomide Badros, et al. American Journal of Medicine. 2002; 112 Biaxin, Low-dose Thalidomide, and Dexamethasone [BLT-D] are Highly Active in Waldenstrom's Macroglobulinemia and Multiple Myeloma Coleman, et al. Abstract Case No. 10-cv-03165 GHK (SSx) 79 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 85 of 141 Page ID #:1357 1 2 3 4 5 6 7 8 9 10 Study or Abstract Title Study or Abstract Author(s) Tosi, et al. Abstract Low Dose Thalidomide and Dexamethasone Are as Effective as Oral Melphalan and Prednisone in Refractory and Relapsed Myeloma Patients Palumbo, et al. Abstract Thalidomide with Dexamethasone for Resistant Multiple Myeloma Weber, et al. Abstract Salvage Therapy with Thalidomide for Patients with Relapsed/refractory Multiple Myeloma Publication 11 198. At Celgene’s direction, Relator and other Celgene sales representatives 12 frequently used these materials to market Thalomid and Revlimid for uses not approved 13 by the FDA. For example, in 2008 and 2009, physicians complained that they were not 14 able to collect stem cells after using Revlimid. Celgene’s management suggested that 15 Relator and other sales representatives use the article entitled “Stem Cell Mobilization 16 with Cyclophosphamide Overcomes the Suppressive Effect of Lenalidomide Therapy on 17 Stem Cell Collection in Multiple Myeloma” on every call in which the physician 18 complained or pushed back due to issues related to collection of stem cells. 19 199. When doctors did not use Revlimid because of its toxicity, Relator and 20 other sales representatives used the article titled “Relationship of Treatment-Related 21 Cytopenias 22 Myelodysplastic Syndromes.” 23 11. 24 and Response to Lenalidomide in Patients With Lower-Risk Celgene Manipulated Continuing Medical Education Programs To Off-Label Market Thalomid And Revlimid 25 200. To further its off-label marketing of Thalomid and Revlimid, Celgene 26 utilized multiple continuing medical education (“CME”) programs led by speakers paid 27 by Celgene to tout the benefits of using Thalomid and Revlimid for non-indicated 28 diseases. In order to encourage physicians to prescribe Thalomid for off-label uses, Case No. 10-cv-03165 GHK (SSx) 80 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 86 of 141 Page ID #:1358 1 Celgene required Relator and other sales representatives to bring CME programs to 2 physicians’ practices in their areas. 3 201. For example, in or about 2004, Celgene provided educational grants for 4 various CME programs concerning Thalomid treatment in MM, MDS, and renal cell 5 carcinoma, among other diseases (at the time, Thalomid was only approved to treat 6 ENL). These CMEs consisted of speakers paid by Celgene to promote Thalomid’s off- 7 label uses. 8 Celgene-sponsored speeches concerning “Recent Developments and Future Directions in 9 the Treatment of Renal Cell Carcinoma.” At the time, Burris was both a paid Celgene 10 In or about 2003 or 2004, Dr. Howard A. Burris, III (“Burris”) gave consultant and a member of Celgene’s Speakers Bureau. 11 202. Celgene pressured Relator and other sales representatives to bring Burris 12 and other CME presenters to medical practices to encourage off-label Thalomid use. In 13 2001, Deena Harding, Relator’s manager, told her that these programs would result in 14 additional sales. Relator, along with her managers Deena Harding and Jeff Rowell, also 15 chose the speakers based on the number of Thalomid (or, later, Revlimid) prescriptions 16 that they wrote or based upon a belief that the speaker would write more prescriptions 17 once he/she was paid to present a CME. For example, Relator knows that Dr. Robert 18 Vescic began writing substantially more prescriptions for Thalomid after Dawn Devore, 19 another sales representative, hired him to present a CME. Ms. Devore told Relator that 20 following the CME, “all he wrote” were Celgene prescriptions. 21 203. Relator kept “Oncology Profiling Notes” which tracked her experiences at 22 various physicians’ practices where she promoted Thalomid. In one set of Relator’s 23 notes from 2004 (i.e., while Thalomid was still indicated solely for ENL), Relator 24 described how she considered bringing Dr. Burris to one medical practice, Kaiser 25 Woodland Hills, to present a renal cell cancer CME, but decided to conduct a CME 26 concerning Thalomid for MM instead, since that practice treated a greater number of 27 MM patients. Relator’s note read: “Met with CME coordinator to bring Dr. Bargolie to 28 Kaiser Woodland Hills for the morning tumor boards . . . I originally planned on Dr. Case No. 10-cv-03165 GHK (SSx) 81 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 87 of 141 Page ID #:1359 1 Burris for renal cell, but Woodland Hills has more MM.” Following the CME, Relator 2 observed an increase in Thalomid prescriptions written for MM at Kaiser Woodland 3 Hills. She saw a similar increase following a CME at Kaiser Panorama City. 4 204. Celgene was well aware that CME programs were an effective way to 5 promote its products for off-label uses. For example, Chad Saward wrote a May 26, 6 2006 email stating that “[o]bviously, if Revlimid gets approval [to treat MM], you will 7 not be able to discuss the role of Revlimid in Newly Dx’d patients, so having a CME 8 accredited resource that discuss all options for Newly Dx’d [diagnosed] patients will be 9 very valuable.” Four days later, on May 30, 2006, Lindsay Luke forwarded Saward’s 10 email to other managers, praising Saward’s message as a “super initiative” and “a good 11 way to be sure the field is aware of the wide array of educational offerings.” 12 205. Celgene urged its sales representatives to promote CME’s, rather than 13 promotional programs. Celgene told sales representatives that a doctor could talk about 14 an off-label use during a CME, but could not do so during a promotional program. 15 Celgene paid presenting physicians to discuss CME’s off-label uses. If the doctor did 16 not, he would be confronted by someone from Celgene. For example, in late 2006 or 17 early 2007, another sales representative in the West Region, Lisette Lopatic, used Dr. 18 Mark Kirschbaum to present a CME at Hoag Hospital in Orange County. 19 confronted him after he failed to mention in a CME the use of Revlimid to treat non 5q 20 deletion MDS patients (Revlimid is only approved by the FDA to treat low- or 21 intermediate risk MDS that is associated with a deletion 5q abnormality). When this 22 was discussed during a conference call of West Region sales representatives, Ms. 23 Lopatic noted that she learned to do this after learning that Shawn Gormish – their 24 manager – had done the same thing when he chased down a doctor following a CME at 25 UCLA. 26 incident with him. She Because Dr. Kirschbaum was in her territory, Relator also discussed this 27 28 Case No. 10-cv-03165 GHK (SSx) 82 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 88 of 141 Page ID #:1360 1 12. 2 Relator And Other Sales Representatives Were Required To Conduct Training Sessions Concerning Thalomid’s Off-Label Uses 3 206. Despite Relator’s lack of formal medical training, she and other Celgene 4 sales representatives were required to present information to fellow sales personnel 5 concerning Thalomid’s use in various off-label diseases. Celgene required that these 6 presentations not only convey medical information, but that they include strategies for 7 encouraging physicians to prescribe for the off-label uses. 8 207. In or about 2003, two of Relator’s fellow sales representatives, Alana 9 Torgelson and Suzanna Zalutko, conducted training on Thalomid’s use in colorectal 10 cancer. The colorectal cancer training materials provided “Selling points of Thalomid 11 use” in colorectal cancer, as well as “Potential Probes” for physicians, including “What 12 is your treatment regimen for [colorectal cancer] [patients]?” Another of Relator’s 13 colleagues, Hank Schwarz, conducted a “Kidney Cancer” training session in or about 14 2004, which included similar hypothetical “probe” questions. In or about 2003 or 2004, 15 Relator conducted a training session concerning Thalomid’s use in prostate cancer. 16 Relator felt uncomfortable giving this presentation, as she had no formal medical 17 training, let alone training concerning prostate cancer. 18 13. 19 Celgene Provided Thalomid and Revlimid To Patients To Treat Off-Label Diseases 20 208. Under the guise of giving away free drugs, Celgene provided Thalomid and 21 Revlimid to patients suffering from the cancers and other diseases that the drugs were 22 not approved by the FDA to treat, in order to get Medicare and Medicaid patients on its 23 desired therapy just prior to enrolling in a government health care plan. 24 209. Celgene provides free Revlimid and Thalomid prescriptions to patients 25 suffering from the cancers and other diseases that the drugs were not approved by the 26 FDA to treat and who are not insured under Medicare Part D but who are eligible for the 27 program. 28 Case No. 10-cv-03165 GHK (SSx) 83 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 89 of 141 Page ID #:1361 1 210. To secure this customer base, Celgene supplies these patients with free 2 Revlimid 3 http://www.celgenepatientsupport.com/ (stating that a “Celgene Patient Support® 4 Specialist” can “[h]elp you apply for the Celgene free medication program”). 5 these patients became eligible for Medicare or Medicaid, they continued to use 6 Thalomid or Revlimid that they previously obtained for free, with the result that those 7 programs paid for the costs of using these drugs for unapproved uses. Celgene possesses 8 records relating to these free prescriptions and accordingly is aware of the resulting false 9 claims submitted to Medicare. 10 C. 11 12 and Thalomid prescriptions. See Celgene Patient Support, Once Sales Representatives Encouraged Physicians to Switch Patients From Thalomid To Revlimid Regardless Of Whether The Patients Were Stable 13 211. Since Revlimid is considerably more expensive than Thalomid ($10,000 per 14 month for Revlimid, compared to up to $2,000 per month for Thalomid), Celgene 15 pressured Relator and other sales personnel to move all patients on Thalomid to 16 Revlimid, even though the products have different indications. (Celgene tried to make 17 the cost increase less unpalatable by increasing the price of Thalomid.) This practice, 18 which serves no medical purpose, places patients at risk of potentially fatal VTE and 19 peripheral neuropathy, among other serious ailments. Furthermore, this practice causes 20 federal, state, and city governments to expend significant, additional funds to cover the 21 far higher cost of Revlimid. And as explained in more detail below, Celgene provided 22 free Revlimid prescriptions to patients that it hopes will soon enroll in a government 23 health program. 24 prescriptions were intended to induce patients to switch from Thalomid to Revlimid – 25 prescriptions that were ultimately paid for by Medicare and other government-funded 26 insurance. Since Revlimid is far more expensive than Thalomid, these free 27 212. In a February 11, 2008 email from Shawn Tomasello, Celgene’s Vice 28 President of Sales, Tomasello refers to the need to “crack” physicians who have Case No. 10-cv-03165 GHK (SSx) 84 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 90 of 141 Page ID #:1362 1 prescribed Thalomid but not Revlimid. 2 circulated a list of physicians who have prescribed Thalomid but not Revlimid and wrote 3 “Let’s get a plan together on what we need to convert these docs . . . I am sure there are 4 nuances for some that we will not crack but other should be ready for ‘cracking.’” In the February 2008 email, Tomasello 5 213. Similarly, Celgene held, and continues to hold, “Rev/Dex” contests, which 6 award the sales representatives and sales teams that successfully move the most MM 7 patients from Thalomid to Revlimid. A November 7, 2008 email from Tomasello to 8 Celgene’s sales force and sales and marketing departments stated, “Looks like Atlantic 9 Central is leading the way in quarterly standings with an average of 6.10 patients 10 converting from Thalomid MM to Revlimid MM . . . Keep up the great work with our 11 customers!” 12 Thalomid to Revlimid earned points that could be exchanged for gifts, including airline 13 tickets, vacations, clothing, appliances, and jewelry. In 2009, Relator used her Rev/Dex 14 contest points to purchase airfare. Representatives who are successful in converting physicians from 15 214. Celgene trained Relator and other sales representatives to move physicians 16 from Thalomid to Revlimid. Relator participated in Phase III training at Celgene’s 17 corporate headquarters in New Jersey from June 26 through June 29, 2007. During this 18 training, she and the other sales representatives were required to “[i]dentify 10 19 prescribers that have written Thalomid MM but not Revlimid MM,” and then list “tactics 20 you will employ with these prescribers” and “probing questions you might ask.” 21 215. Celgene tracked these conversions and presented the results to its sale force. 22 For example, at its April 13-14, 2010 West Region Cross Functional Meeting, the 23 company presented data for each representative’s conversion. Relator accomplished 73 24 conversions between April 2009 and March 2010 and her “% Rev Conversions” was 25 “26.0%.” 26 216. Doctors were often reluctant to switch MM patients from Thalomid to 27 Revlimid as the drugs were in the same class. For example, Drs. Anthony Stein and 28 David Snyder at City of Hope Hospital told Relator that “it’s the same drug” while Case No. 10-cv-03165 GHK (SSx) 85 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 91 of 141 Page ID #:1363 1 another doctor told her “under the microscope, it’s the same drug.” Thus, in order for 2 Celgene to accomplish its goal of switching patients from Thalomid to Revlimid, it was 3 forced to misbrand Revlimid. For example, during the Phase III Training Celgene 4 directed Relator to make unsubstantiated claims concerning the supposed superiority of 5 Revlimid to Thalomid. While there are no head-to-head trials comparing Revlimid’s 6 versus Thalomid’s efficacy in, for instance, MM patients, Celgene specifically instructed 7 Relator to make claims to physicians that Revlimid is a more effective medication for 8 the disease. Relator was also instructed to claim that Revlimid had fewer side effects 9 than Thalomid and that it was more potent. These representations constituted unlawful 10 misbranding since they were not supported by Revlimid’s FDA-approved labeling. 11 217. In an effort to begin convincing physicians to switch their patients from 12 Thalomid to Revlimid, Celgene marketed Revlimid to physicians in this fashion prior to 13 receiving FDA approval for the drug. 14 D. 15 16 Celgene Manipulated the FDA Mandated Patient Protection Programs to Market Its Products Off-Label 1. 17 Celgene Created a Position, the Patient Support Coordinator, to Assist Patients in obtaining Government Funding for these Drugs 18 218. In 2006, Celgene created the Patient Support Coordinator program (the 19 “PSC”).5 20 Thalomid, Revlimid and other Celgene drugs. Sales representatives, such as Relator, 21 informed physicians about the PSC anticipating that the physicians will then refer their 22 patients to the program. 23 Specialists (“PSSs”) who assist patients in enrolling in Medicare or Medicaid and help 24 patients receive reimbursement from government-funded insurance. The primary PSS 25 responsible for Relator’s sales district was Samuel Vasquez (“Vasquez”). The PSC has The PSC provides “reimbursement assistance” to patients prescribed The program includes individuals called Patient Support 26 27 28 5 Celgene later changed PSC’s name to “Celgene Patient Support.” Case No. 10-cv-03165 GHK (SSx) 86 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 92 of 141 Page ID #:1364 1 caused Medicare and Medicaid to pay for a greater number of off-label Thalomid and 2 Revlimid prescriptions. 3 219. Celgene sales representatives touted the PSC to physicians in order to 4 encourage them to prescribe Thalomid and Revlimid. 5 National Sales meeting in 2009 in Scottsdale, Arizona, sales representatives were told to 6 encourage physicians to enroll as many patients as possible in the PSC. A prime 7 example of Celgene’s efforts with the PSC is contained in a November 17, 2009 email 8 sent by Katherine Stultz (“Stultz”) – Celgene Director of Patient Support and 9 Reimbursement Services – to Celgene’s national sales force in which Stultz directs 10 Celgene’s sales force to distribute PSC materials concerning Medicare enrollment to 11 physicians. Specifically, Stultz writes the following: 12 13 14 15 16 17 Moreover, at the Celgene Next week each of you will receive an auto shipment of the “Reminder Medicare Part D enrollment cards” . . . Please utilize these cards to remind your office this is the only time of year to enroll patients in Medicare Part D . . . Most important – these cards are a trigger to come to our team for assistance if they or their patients have questions about coverage of a Celgene product in any Medicare Part D plan. (emphasis in original). 18 220. Celgene’s efforts have been very successful. A September 28, 2009 email 19 from Vasquez states that “there is a rise in the number of cases I am currently 20 handling . . . due to the Patient Support initiative to enroll patients into Medicare Part 21 D.” Vasquez’s email includes a chart showing Thalomid and Revlimid patients for 22 whom Vasquez is assisting with Medicare and Medicaid enrollment. Prior to the Patient 23 Support initiative, roughly one-third of Revlimid and Thalomid takers were enrolled in 24 the PSC. 25 221. The Patient Support Specialists were acutely aware which prescriptions 26 were being paid by Medicare, Medicaid and other government payors since this was 27 their job. Celgene passed on this information to its sales force in an effort to generate 28 additional sales, including its off-label sales. As a result of Celgene’s introduction of the Case No. 10-cv-03165 GHK (SSx) 87 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 93 of 141 Page ID #:1365 1 Patient Support Specialists, it possessed detailed information regarding prescriptions 2 submitted to Medicare, Medicaid and other government payors. Thus, Celgene knew of, 3 for example, the Revlimid prescriptions submitted to Medicare that were prescribed by 4 Dr. Leland Green on January 10, 2007; Dr. David Leibowitz on December 26, 2006 and 5 on January 18, 2007; Dr. Jeffery Wolf on January 15, 2007 and on January 31, 2007; Dr. 6 Veena Charu on January 16, 2007 and on May 2, 2007; Dr. Samar Shihabi on February 7 1, 2007; Dr. Michael Kosmo on March 6, 2007; Dr. Howard Chen on March 7, 2007; 8 Dr. John Kailath on March 8, 2007; Dr. Jason Salgnick on March 14, 2007; Dr. John 9 Gunnel on March 12, 2007; Dr. David Bodkin on March 23, 2007; Dr. Patrick Sheeny 10 on April 6, 2007 and on May 30, 3007; Dr. Jeffery Shinoda on April 11, 2007; Dr. 11 Jonathan Blitzer on April 17, 2007; Dr. John Siebel on April 16, 2007; Dr. William Read 12 on April 23, 2007; Dr. Salomon Hamburg on April 26, 2007; Dr. Michelle Rooney on 13 April 26, 2007; Dr. Madhu Jodhani on May 1, 2007; Dr. Kathleen Turner-Hubbard on 14 May 14, 2007 and on May 30, 2007 and on June 27, 2007; Dr. John Clune on May 16, 15 2007; Dr. Marilyn Norton on June 5, 2007; Dr. Lynn Bemiller on June 18, 2007; Dr. 16 Anna Ganeles on June 28, 2007; Dr. Robert Klein on June 22, 2007; Dr. Jareed Manscor 17 on July 2, 2007; and Dr. Harry Menco on July 12, 2007. 18 2. 19 Celgene Manipulates RevAssist To Cause Medicare And Medicaid To Pay For Off-Label Revlimid Prescriptions 20 222. As previously alleged, due to the high risk of birth defects with Thalomid 21 and Revlimid, the FDA requires Celgene to implement strict distribution systems for 22 each drug. 23 operates in the following manner. Revlimid prescribers must comply with the RevAssist system, which 24 223. First, the physician uses RevAssist software (loaded onto a computer via 25 CD and accessible online) to create a Patient-Physician Agreement Form (“PPAF”). 26 The PPAF has a patient information page, where the physician selects the patient’s 27 “Diagnosis” from a “drop-down” menu of ICD-9 codes, which are three-to-five digit 28 Case No. 10-cv-03165 GHK (SSx) 88 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 94 of 141 Page ID #:1366 1 codes indicating the disease for which a patient is receiving Revlimid. This is a one- 2 time process for each new Revlimid patient. 3 224. The physician then completes either an online or telephone survey 4 confirming that the patient has been counseled about the risk of birth defects and the 5 need to use protection if engaging in sex while taking Revlimid. After completing the 6 survey, the physician receives an authorization number from Celgene that allows him or 7 her to write the prescription. A physician must complete this survey every time he or 8 she writes a prescription. Physicians may only write a prescription for a one-month or 9 less supply of Revlimid, and may not include any refills. Thus, if a patient takes 10 Revlimid long-term, the physician must write a new prescription every month. 11 225. Once the physician writes a prescription, RevAssist requires the physician 12 to complete a dedicated RevAssist prescription form. This form can be generated 13 through RevAssist software, faxed to the physician from Celgene, or downloaded from 14 Celgene’s website. The form has a blank field for the “Patient’s Diagnosis Code (ICD-9 15 Code).” 16 226. The physician is then required to submit the prescription to a “specialty 17 pharmacy” that is specifically licensed to supply Revlimid. 18 pharmacy receives the prescription form, the pharmacist must contact Celgene and 19 confirm the physician’s authorization code. When the specialty 20 227. In or about 2006, shortly after Revlimid’s launch, Relator’s manager, 21 Gormish, directed Relator and other sales representatives to “change the [ICD 9] codes” 22 on Revlimid prescriptions that were written for off-label indications to reflect that the 23 prescriptions were for on-label uses. At the 2009 national sales meeting in Scottsdale, 24 Arizona, during a “district break-out session,” the manager of the West Region’s PSC, 25 Tom Girrardi, directed the West Region sales representatives to change the codes on 26 physicians’ Revlimid prescriptions. 27 228. Relator refused to take part in the scheme. In October 2008, Relator wrote 28 a letter to Celgene stating that she understood changing ICD-9 codes was unlawful. Case No. 10-cv-03165 GHK (SSx) 89 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 95 of 141 Page ID #:1367 1 Moreover, Relator participated as a third party in a deposition brought by a former 2 Celgene sales representative who claimed unlawful discharge in the summer of 2009. 3 During the deposition, Relator reiterated her position concerning changing ICD-9 4 codes.6 5 229. Since Relator stalwartly refused to participate in Celgene’s unlawful code- 6 changing practice, she never inquired as to how she could change physicians’ 7 prescription forms. 8 activities within Celgene that suggest the various ways Celgene personnel accomplish 9 this task. 10 Nevertheless, from 2006 through 2011, Relator has observed 230. Without FDA approval, Celgene modified its RevAssist program under the 11 guise of “assisting” physicians with RevAssist’s cumbersome process. 12 RevAssist, Celgene provides physicians with a specific RevAssist prescription form. 13 But Celgene allows at least one specialty pharmacy, PharmaCare Specialty Pharmacy 14 (“PharmaCare”), to create its own prescription form for physicians who write Revlimid 15 prescriptions. This new prescription form requires the physician to check one of two 16 boxes that include a corresponding on-label ICD-9 code for either MDS or MM. The 17 physician can also check a box for “Other” which is adjacent to a blank line. Under 18 19 20 21 22 23 24 25 26 27 28 6 In response to her opposition to Celgene’s violations outlined in this Complaint, Relator, for the first time in her career at Celgene, received poor performance reviews. For instance, during the week of March 6, 2010, Gormish provided Relator with her 2009 performance evaluation, which stated that Relator “needs improvement.” When Relator inquired about the basis for her poor performance review, Gormish provided very little explanation. Furthermore, Relator asked Gormish for her current “ranking” among Celgene’s sales force. Gormish was initially unable to provide Relator her current ranking, instead telling her that her rank fell somewhere between 80 and 100 out of 102 total sales representatives. On March 10, 2010, Gormish forwarded to Relator an email from a member of Celgene’s West Region that stated that Relator was then-currently ranked 98th ranked (out of 102) sales representatives within the Company. According to Relator, this sales rank is incorrect, as she out-performed many of her peers within the Company. Case No. 10-cv-03165 GHK (SSx) 90 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 96 of 141 Page ID #:1368 1 231. The PharmaCare prescription form is laid out in this manner to encourage 2 physicians to check a box that corresponds to an on-label ICD-9 code, even if the 3 prescription is off-label. 4 pharmacists may “doctor” prescriptions where the “Other” box is checked, and fill in an 5 on-label ICD-9 code. 6 Medicaid, other government payors, or private insurers including those in California. 7 Relator and her fellow sales representatives have received intense pressure from 8 Gormish to encourage physicians to send all prescriptions to PharmaCare, which 9 distributes this alternate prescription form. Moreover, Relator believes that PharmaCare specialty These prescription forms are then submitted to Medicare, 10 232. Similarly, Relator learned that shortly before a patient’s prescription ends, 11 PharmaCare may be sending physicians pre-prepared prescription forms that merely 12 require the physician to sign for a patient’s refill. These forms contain on-label ICD-9 13 codes, which most physicians will not bother to change. 14 233. Relator is also aware that Greater Sacramento Specialty Pharmacy engaged 15 in similar practices, including code manipulation, as PharmaCare. Other RevAssist 16 specialty pharmacies include Walgreens Specialty Pharmacy, Caremark Connect, Aetna 17 Specialty Pharmacy, McKesson Specialty Pharmacy, BioScrip Pharmacy, US 18 Bioservices, Medco Special Care Pharmacy, Medmark Pharmacy, Advanced Care 19 Scripts, and Axium Healthcare Pharmacy, Inc. 20 234. Additionally, Relator is aware of at least one practice in the Los Angeles 21 area that has had its Revlimid prescriptions for prostate cancer patients changed to on- 22 label, MDS ICD-9 codes. Specifically, the Compassionate Oncology Medical Group in 23 Los Angeles, run by Dr. Bob Liebowitz, predominately treats prostate cancer patients. 24 Celgene’s records indicate that Dr. Liebowitz is one of the highest-volume prescribers of 25 Revlimid for MDS. Dr. Liebowitz’s off-label Revlimid prescriptions have, in fact, been 26 unlawfully altered. 27 28 Case No. 10-cv-03165 GHK (SSx) 91 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 97 of 141 Page ID #:1369 1 E. 2 Celgene Pays Kickbacks To Physicians To Prescribe Thalomid and Revlimid And To Encourage Other Physicians To Prescribe The Drugs 3 4 235. The federal Medicare Anti-Kickback Statute makes it unlawful to pay 5 remuneration in any form to induce the generation of business reimbursable by 6 Medicare, Medicaid, or any other government-funded insurance program. 7 nonetheless made kickbacks a key part of its strategy to induce Thalomid and Revlimid 8 prescriptions. Celgene 9 236. Celgene’s marketing strategy also included the allocation of substantial 10 resources to educate physicians and other health care professionals about off-label uses 11 of Thalomid and Revlimid. The 2004 Business Plan – West Region authored by Larry 12 Bishop and described in detail above, recognized that “[w]e can’t sell clinicians on 13 Thalomid, because most don’t have an indication. What we really do is make sure that 14 those who have the targeted patient population appreciate the product mechanism of 15 action, know its possible clinical effect, and know how to prescribe it.” It therefore 16 instructed the sales force to “utilize speaker programs, grant request funds and 17 entertainment budgets strategically for the education required to assure that patients and 18 physicians understand the value of Thalomid therapy” and prescribe Thalomid. Celgene 19 did this. 20 237. Celgene repeatedly hired doctors to promote off-label uses of Thalomid and 21 Revlimid at conferences attended by practicing physicians. For example, as set forth in 22 Monica Blackstone’s letter to Dr. Fine, Celgene paid Dr. Fine to speak at the 2004 23 American 24 “THALOMID/REVLIMID’s clinical developments and new approaches as a potential 25 therapy in gliobastomas” (brain cancers). Ms. Blackstone’s letter, written on or about 26 May 26, 2004, also requested Dr. Fine’s tax identification number so that Celgene could 27 pay him to promote this off-label use to other doctors attending the ASCO meeting. 28 Then, as now, neither of Celgene’s products were approved by the FDA to treat Society Case No. 10-cv-03165 GHK (SSx) of Clinical Oncology 92 THIRD AMENDED COMPLAINT (ASCO) meeting about Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 98 of 141 Page ID #:1370 1 gliobastomas. In 2004 and 2005, Celgene also hired Dr. Gordon to speak at ASCO on 2 using Thalomid to treat renal cell cancer; Dr. Whu to speak at ASCO on Thalomid to 3 treat metastic malignant melanoma; Dr. Attal to speak at the American Society of 4 Hematology (ASH) national meeting regarding Thalomid maintenance; and Dr. Palumbo 5 to speak about using Thalomid and Revlimid to treat newly diagnosed multiple 6 myeloma. 7 238. Immediately after Revlimid’s launch, Relator and other sales 8 representatives began receiving intense pressure to find physicians Celgene could pay to 9 promote Revlimid. Celgene sales representatives were required to take these physicians 10 to other medical practices where the physicians could promote Revlimid use. Celgene’s 11 payments to physicians for the talks constitute illegal kickbacks meant to directly and/or 12 indirectly encourage the writing of Revlimid prescriptions. 13 239. Celgene designates certain physicians as “Thought Leaders.” A Thought 14 Leader is an experienced, respected physician who writes a high volume of Revlimid 15 prescriptions. After Celgene designates a physician as a Thought Leader, the Thought 16 Leader is connected with a company called Envision, which trains the Thought Leaders 17 to give presentations, and facilitates Thought Leader programs. Celgene refers to the 18 programs as “Envision Programs.” Envision Programs can take nearly any form. More 19 specifically, an Envision Program can be a one-on-one, in-office conversation between a 20 Thought Leader and another physician or a breakfast, lunch or dinner presentation either 21 within or outside of a physician’s practice. Physicians are paid from $1,600 to $4,000 22 for each Envision Program he or she conducts. Certain physicians were paid even more. 23 For example, Relator is aware of a Dr. Berenson in California who receives upwards of 24 $10,000 to conduct Envision Programs. As part of Celgene’s Envision speaker training, 25 Celgene and Envision developed written material, including PowerPoint presentations 26 and slides, for use by physicians at speaker’s programs. Celgene encouraged its sales 27 force to provide the materials to speakers who lectured on the off-label uses of Thalomid 28 Case No. 10-cv-03165 GHK (SSx) 93 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 99 of 141 Page ID #:1371 1 and Revlimid. Celgene devoted substantial resources to these Envision Programs. For 2 example, its budget for just Envision programs in 2004 was $910,500. 3 240. From 2006 through 2009, Relator was required to facilitate 15 or 16 4 Envision Programs per year. Within Relator’s sales district, total Envision Program 5 goals are generally to exceed 150 programs per year. 6 encouraged Relator and other sales representatives to hold Envision Programs at 7 physicians practices where Celgene can get the most bang for its buck. Multiple emails 8 from Relator’s manager ordered Relator and her fellow sales representatives to “target” 9 physicians who are high Dacogen (a competitor MDS drug) and Velcade (a competitor 10 Tellingly, Celgene strongly MM drug) prescribers in an effort to convert those physicians to Revlimid.7 11 241. For instance, an August 31, 2009 email from Relator’s then-district sales 12 manager, Shawn Gormish, to Relator and other sales representatives stated that sales 13 representatives should focus on “opportunities in high Velcade or Dacogen accounts” 14 and to “capitalize on ROI” (i.e., return on investment). For 2009, Celgene’s budget for 15 Envision Programs was $5 million. In 2008, Relator alone facilitated more than $45,000 16 in Envision Programs. 17 242. Celgene routinely set timetables for representatives to exhaust their speaker 18 budgets, so as to ensure that representatives were devoting enough time and money to 19 this key component of Celgene off-label message and kickback plans. Relator and other 20 sales representatives were praised for holding high numbers of Envision Programs and 21 were penalized for failing to meet certain quotas. 22 Evaluation, Gormish praised Relator for developing Thought Leaders and utilizing 23 Envision Programs, writing “You developed the following advocates: In Relator’s 2006 Performance Dr. George 24 25 26 27 28 7 Dacogen is FDA-approved for treatment all types of MDS, while Velcade is indicated for all types of MM. As stated throughout the Complaint, Revlimid is indicated solely for low to intermediate risk MDS with deletion 5q cytogenic abnormality, and previously treated MM. By encouraging sales representatives to target Dacogen and Velcade prescribers and market Revlimid as a competitor drug, Celgene further caused its sales representatives to off-label market Revlimid. Case No. 10-cv-03165 GHK (SSx) 94 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 100 of 141 Page ID #:1372 1 Somlo and Dr. Amrita Krishnan, both attended MM speaker training and Dr. Somlo also 2 attended the MDS advisory board . . . Bev, I am especially proud of this effort . . . 3 [T]he envision programs worked for you.” Relator was similarly praised in her 2008 4 Performance Evaluation: “[O]f particular note of Business management is your ability to 5 use your envision promotional programs which you have completed 16 envision 6 programs . . . In 2009, continue to analyze your business needs and place your envision 7 programs.” 8 243. An August 25, 2008 email from Gormish praised Relator and two other 9 sales representatives who had “planned or executed the most” Envision Programs. The 10 email continues by encouraging other sales representatives to do more programs: “Per 11 the guidance on our last Conference call, I would like everyone to end up with at least 12 16, those who have 12 or more, please keep planning and executing where your territory 13 needs . . . The district average per territory, should at least [sic] 16 programs per HOC. 14 That would place the great Hollywood district at 160 for the year.” 15 244. Celgene also violated the anti-kickback statute by unlawfully promoting 16 Revlimid through its “Speaker Corps” speaker’s series. Celgene engaged numerous 17 speakers who frequently spoke on predetermined topics areas such as “Recent 18 Developments and Future Directions in the Treatment of Multiple Myeloma,” or “The 19 Role of Revlimid (lenalidomide) in Multiple Myeloma.” 20 speakers for Celgene spoke frequently, often multiple times a day, and received 21 generous compensation from Celgene for their often limited speaking engagements. 22 Celgene’s most active Revlimid speakers, many considered “core faculty” for the 23 Speaker Corps series include: Steven T. Rosen, MD, Kenneth Anderson, MD, Bart 24 Barlogie, MD, PhD, James R. Berenson, MD, Gregory Berk, MD, Ivan Borrello, MD 25 Asher Chanan-Khan, MD, Raman K. Desikan, MD, Philip Greipp, MD, Mohamad A. 26 Hussein, MD, Sundar Jagannath, MD, Robert A. Kyle, MD, Alan List, MD, Sangar 27 Lonial, MD, Jayesh Mehta, MD, Nikhil Munshi, MD, Prabhjit Purewal, MD, Azra Raza, 28 MD, Paul Richardson, MD, Eric K. Rowinsky, MD, David S. Siegel, MD, PhD, Seema Case No. 10-cv-03165 GHK (SSx) 95 THIRD AMENDED COMPLAINT The doctors engaged as Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 101 of 141 Page ID #:1373 1 Singhal, MD, Gordon Srkalovic, MD, PhD, Stefano Tarantolo, MD, Steven Treon, MD, 2 MA, PhD, Robert A. Vescio, MD, and Thomas Witzig, MD. 3 245. Several of these speakers were engaged multiple times by Relator or other 4 speakers in Relator’s district. For example, Dr. James R. Berenson was engaged to 5 speak 22 times between May 2009 and April 2010. Quite often, Dr. Berenson spoke 6 multiple times in one day giving the same speech for the same Celgene sales 7 representative. Another speaker, Dr. Azra Raza was listed as – and paid for – giving 8 four speeches for the same representative on the same day. 9 246. Celgene analyzed its “investment” in speakers both formally and 10 informally. Sales representatives also paid close attention the prescribing of doctors 11 who spoke and doctors who attended the speaker programs. For example, as described 12 above, Dr. Robert Vescic began writing substantially more prescriptions for Thalomid 13 after Celgene began paying him to speak. 14 247. Celgene also analyzed sales data relating to its speakers at a corporate level. 15 For example, a 2009 PowerPoint on its “Speakers Bureau” includes slides describing it 16 “Return on Investment Analysis” and its efforts to “quantify any additional revenue of 17 speaker bureau programs.” Celgene’s also evaluated its sales force, in part, based upon 18 the increase in prescriptions written by paid speakers. 19 evaluation, she is praised for development of “Dr. Berenson as a speaker and advocate 20 for Celgene. You may not notice the rise in his TRXs [total prescriptions] in MM for his 21 trial. However, the TRXs in the district took a dramatic upswing for new patient starts 22 in November and December. This aided greatly in the district making its goal.” In Dawn DeVore’s 2009 23 248. All of Celgene’s payments to physicians to speak were intended, at least in 24 part, to induce them to write additional prescriptions for Celgene’s products. Robert 25 Pearl, the executive director and CEO of the Permanente Medical Group, Kaiser 26 Permanente, recently wrote in the Wall Street Journal that financial relationships 27 between pharmaceutical and medical device companies and physicians “are formed 28 under the guise of advancing education and innovation. But they are really part of a Case No. 10-cv-03165 GHK (SSx) 96 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 102 of 141 Page ID #:1374 1 thinly veiled promotional strategy designed to increase sales, particularly for expensive 2 products with high profit margins.” Celgene’s payments described above likewise were 3 part of its marketing plans to increase the number of prescriptions written for its 4 products by paying doctors to prescribe Thalomid and Revlimid. 5 249. In addition to paying doctors under the guise of speaker programs, Celgene 6 made payments to doctors who could have an even broader impact on the market for 7 honest medical information. 8 favorably Thalomid and Revlimid and so has made payments to the doctors advising the 9 compendia. For example, of the 30 doctors used by the National Comprehensive Cancer 10 Network (NCCN) compendia to prepare its section on Multiple Myeloma, 16 had 11 received money from Celgene. Three of these 16 – Dr. Kenneth Anderson, Dr. Seema 12 Singhal and Dr. Steven Treon – were also considered “core faculty” for the Speaker 13 Corps series as described above. Celgene worked to get the drug compendia to treat 14 F. 15 250. Throughout Relator’s tenure at Celgene, she and other sales representatives 16 have been immersed in educational materials concerning government insurance 17 programs. In or about 2006, Celgene sent Relator a booklet entitled “Reimbursement in 18 the Oncology Market.” 19 Chemotherapeutic Drugs,” that states “[b]ecause the average age of a multiple myeloma 20 patient is 65 or greater, Medicare is the primary payer for most patients and is therefore 21 essential to Celgene’s business.” The booklet continues with a discussion of, inter alia, 22 Medicare and Medicaid. Celgene Directly Targets Federal And State Healthcare Dollars The booklet contains a section entitled “Key Payers for 23 251. Moreover, due to the high cost of Thalomid and Revlimid, Celgene knew it 24 could raise the volume of Thalomid and Revlimid prescriptions by assuring doctors that 25 government programs could mitigate the costs of the drugs. For example, in or about 26 2006, Celgene provided Relator with a DVD entitled “Medicare Part D and Beyond: 27 Facilitating Patient Access to Novel Therapeutics in Oncology.” 28 Relator and other sales personnel to provide this DVD to physicians to help them better Case No. 10-cv-03165 GHK (SSx) 97 THIRD AMENDED COMPLAINT Celgene directed Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 103 of 141 Page ID #:1375 1 understand how Medicare could pay for Thalomid and Revlimid. Similarly, in 2008, 2 Relator was praised by Gormish for her “thorough understanding of Reimbursement for 3 Medicare [P]art D,” which she was able to effectively communicate to physicians. 4 252. As suggested above, a large percentage of Revlimid and Thalomid 5 prescriptions are paid for by Medicare. As Celgene’s President and Chief Operating 6 Officer, Robert J. Hugin, stated on January 29, 2009 Earnings Conference Call, a 7 majority of [Revlimid] patients are most likely Medicare.” Similarly, an April 1, 2009, 8 Credit Suisse analyst report states that “Medicare . . . patients account for the lion’s 9 share of [Celgene’s] revenue.” 10 1. Celgene Targeted Veterans Administrations And TRICARE 11 253. In addition to directly targeting Medicare and Medicaid dollars, Celgene 12 targeted Veterans Administration patients. A 2007 Company newsletter titled, “What’s 13 Up In Summit?” (a reference to Celgene’s headquarters in Summit, New Jersey) 14 provides “Tips for Working a VA” for sales representatives who are “having trouble 15 meeting with [their] VA Hematologists/Oncologists.” 16 17 254. Indeed, Relator promoted Thalomid and Revlimid for off-label uses at the North Hills VA in North Los Angeles County, CA. 18 255. In or about 2004, Relator learned that the North Hills VA treated many MM 19 patients, but with VAD, a combination of generic chemotherapy drugs.8 Around that 20 time, Celgene informed Relator that TRICARE offered a minimal $5 co-pay on the 21 otherwise expensive Thalomid (some TRICARE beneficiaries can be treated at VA 22 facilities). Relator, however, experienced great difficulties gaining access to physicians 23 at this VA, notwithstanding that she had informed physicians of patients’ mere $5 co- 24 pay for their Thalomid prescriptions. Accordingly, at a 2004 Diamond Club Meeting, 25 Relator approached then-COO, Barer, concerning her difficulties persuading VA 26 physicians to prescribe Thalomid for MM. Barer agreed with Relator that it was an 27 28 8 In 2004, Thalomid was not indicated for MM. Case No. 10-cv-03165 GHK (SSx) 98 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 104 of 141 Page ID #:1376 1 interesting problem, and then allowed other sales representatives to interject and offer 2 their strategies for penetrating VAs. 3 contemplate the issue and see if he could come up with any solutions. Barer told Relator that he would have to 4 256. Celgene’s marketing to TRICARE and VA physicians was successful. As a 5 result of Celgene’s RevAssist and S.T.E.P.S. programs and its Patient Support 6 Specialists, Celgene possesses detailed records of the false claims paid by the VA and 7 TRICARE including but certainly not limited to TRICARE prescriptions of Revlimid 8 written by Dr. John Wilkinson on April 3, 2007; Dr. David Bodkin on April 1, 2007; Dr. 9 David Campbell on May 7, 2007; Dr. Ram Lanchandani on May 11, 2007; Dr. Jareed 10 Manscor on May 15, 2007; Dr. John Kailath on May 29, 2007; Dr. Nanda Miswas on 11 June 25, 2007; Dr. Carolyn Wild on July 10, 2007 and on August 14, 2007; Dr. Peter 12 Wittlinger on August 13, 2007; Dr. Dennis Hillard on August 27, 2007; Dr. Veena 13 Charu on September 4, 2007; Dr. Kai Zu on November 1, 2007; and Dr. Phillip 14 Dreisbach on November 14, 2007. 15 16 2. Celgene Targeted Private Payors, Including Insurers In California 17 257. In addition to directly targeting Medicare and Medicaid dollars and VA and 18 TRICARE funds, Celgene also targeted private insurers, including those in California. 19 Because private insurers were viewed as critical to the success of Revlimid and 20 Thalomid, Celgene targeted private insurers including, but not limited to, Kaiser 21 Permanente, United Healthcare, Healthnet, HMSA, Excellus, Highmark, Horizon, 22 Coventry, WellCare, Aetna, Cigna, and MemberHealth. 23 258. For example, as early as 1999, Celgene began targeting private insurers in 24 California. Alana Mintzer’s business plan for the second quarter of 1999, for example, 25 stated that she would “focus and identify all the key players within Kaiser and the major 26 Managed Care Groups to seek approval and reimbursement.” Kaiser refers to Kaiser 27 Permanente, one of the nation’s largest not-for-profit health plans, that provides health 28 Case No. 10-cv-03165 GHK (SSx) 99 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 105 of 141 Page ID #:1377 1 insurance to more than 9.1 million people, almost 7 million of whom are located in 2 California. Kaiser is headquartered in Oakland, Calif. 3 259. In 2004, as Celgene began to prepare to “launch” Revlimid, it targeted 4 Kaiser by assigning Alana S. Torgelson, by than a Corporate Account Manager, to as 5 she wrote in a July 12, 2004 email, “work[ ] the account at a national level.” At the 6 same time, the company’s Government Affairs, Corporate Account Management, Sales 7 Operations and Customer Care Center departments were preparing a Thalomid 8 “Multiple Myeloma Launch Plan.” As part of that plan, Celgene decided to “[i]nclude 9 Kaiser KOLs [key opinion leaders] on Celgene Roadmaps and speaker programs” and 10 “[i]nclude Kaiser KOLs in Ad Boards in all disease states.” In other words, in order to 11 get Kaiser physicians to prescribe Thalomid, it was going to pay key doctors at Kaiser. 12 This launch plan also described the Company’s efforts to influence doctors at PacifiCare 13 Health Systems, Cigna and Aetna. 14 260. Celgene’s targeting of Kaiser was successful. In the first two months of 15 2006, Celgene held 18 “in-services” at Kaiser, and Celgene became a “Vendor” for 16 Kaiser Permanente. As explained in Celgene’s Government Affairs operations report 17 for the week of February 13, 2006, this was important as it allowed Kaiser’s orders to be 18 placed directly with Celgene and ensured that “Revlimid will be covered in all plans 19 with a branded co-pay ….” 20 261. As set forth in Celgene’s Managed Care team 2008 business plan, the 21 company attempted to have these insurers pay for its products by blanketing them with 22 speaker programs, continuing education programs, and clinical presentations designed to 23 educate these insurers about, among other things, Revlimid indications. 24 262. Through Celgene’s targeting efforts, Kaiser Permanente went on to become 25 a key account bringing in $33 million in revenue a year to Celgene by 2009. As 26 explained by Sam Wissa, a national account manager, in a April 19, 2010 email, this $33 27 million in yearly sales “blows away the Rev volume of all of England” and is starting to 28 “look a lot like the volume of the entire VA in the US.” Case No. 10-cv-03165 GHK (SSx) 100 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 106 of 141 Page ID #:1378 1 COUNT ONE Federal False Claims Act, 31 U.S.C. § 3729(a)(1)(A)9 2 3 4 5 6 263. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 264. This is a claim for treble damages and civil penalties under the False Claims Act, 31 U.S.C. § 3729(a)(1). 7 265. By virtue of the conduct described above, Defendant knowingly caused to 8 be presented to Medicaid, Medicare, and other Government funded health insurance 9 programs false or fraudulent claims for the improper payment or approval of 10 11 12 13 14 prescriptions for off-label uses of Thalomid and Revlimid. 266. The United States, unaware of the falsity or fraudulent nature of the claims that Defendant caused, paid for claims that otherwise would not have been allowed. 267. By reason of these payments, the United States has been damaged, and continues to be damaged, in a substantial amount. 15 COUNT TWO Federal False Claims Act, 31 U.S.C. § 3729(a)(1)(B)10 16 17 18 19 20 268. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 269. This is a claim for treble damages and civil penalties under the False Claims Act, 31 U.S.C. § 3729(a)(1)(B). 21 270. By virtue of the conduct described above, Defendant knowingly caused to 22 be made or used false records or statements that caused false claims to be paid or 23 approved by the United States Government. 24 25 26 27 28 9 To the extent wrongdoing occurred prior to May 20, 2009, this Complaint should be deemed to include violations of the Federal False Claims Act prior to its recent amendments, .e.g., 31 U.S.C. § 3729(a)(1). 10 To the extent wrongdoing occurred prior to May 20, 2009, this Complaint should be deemed to include violations of the Federal False Claims Act prior to its recent amendments, .e.g., 31 U.S.C. § 3729(a)(2). Case No. 10-cv-03165 GHK (SSx) 101 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 107 of 141 Page ID #:1379 1 2 3 4 5 6 7 8 9 10 271. The United States, unaware of the falsity or fraudulent nature of the claims that Defendant caused, paid for claims that otherwise would not have been allowed. 272. By reason of these payments, the United States has been damaged, and continues to be damaged, in a substantial amount. COUNT THREE California False Claims Act., Cal. Gov’t Code § 12651 et seq. 273. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 274. This is a claim for treble damages and civil penalties under the California False Claims Act. Cal. Gov’t Code § 12651 et seq. 11 275. By virtue of conduct described above, Defendant knowingly caused to be 12 presented to the California Medicaid Program (i.e., Medi-Cal) false or fraudulent claims 13 for the improper payment or approval of prescriptions for off-label uses of Thalomid and 14 Revlimid. 15 276. The California Medicaid Program, unaware of the falsity or fraudulent 16 nature of the claims caused by Defendant, paid for claims that otherwise would not have 17 been allowed. 18 19 20 21 22 23 24 25 277. By reason of these payments, the California Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT FOUR California Insurance Frauds Prevention Act, Cal. Ins. Code § 1871.7 278. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 279. This is a claim for treble damages and civil penalties under the California Insurance Frauds Prevention Act, Cal. Ins. Code § 1871.7. 26 280. By virtue of the conduct described above, Defendant caused to be 27 presented, or knowingly assisted or conspired in presenting or causing to be presented, 28 to the insurers in the State of California fraudulent claims that were induced by Case No. 10-cv-03165 GHK (SSx) 102 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 108 of 141 Page ID #:1380 1 payments of kickbacks to physicians, in violation of Penal Code § 550(b)(1), among 2 other provisions. 3 281. Moreover, by virtue of the conduct described above, Defendant knowingly 4 caused to be made fraudulent bills intended to be presented to the insurers in connection 5 with, or in support of, claims for the payment of compensation under contracts of 6 insurance knowing that the statements contained false or misleading information 7 concerning material facts, in violation of Penal Code § 550(b)(2), among other 8 provisions. 9 282. By virtue of the kickbacks, misrepresentations, and submissions of non- 10 reimbursable claims described above, Defendant knowingly presented or caused to be 11 presented false or fraudulent claims for the payment of a loss or injury, including 12 payment of a loss or injury under a contract of insurance; prepared, made, and 13 subscribed writings, with the intent to present or use them, or to allow them to be 14 presented, in support of false or fraudulent claims; and made or caused to be made false 15 or fraudulent claims for payment of a health care benefit in violation of Penal Code § 16 550 (a)(1), (5), and (6), among other provisions. 17 283. By virtue of the conduct described above, Defendant caused false claims to 18 be submitted to insurance companies for the payment of health care benefits. Had the 19 private insurance companies known that prescriptions for Defendant’s drugs were 20 written because physicians had been paid kickbacks by Defendant to do so, and/or that 21 Defendant had made statements containing false or misleading information concerning 22 material facts these companies would not have provided reimbursement for these 23 prescriptions. 24 284. By virtue of the conduct described above, Defendant’s conduct represents 25 the inducement of health care benefits through a pattern and practice of fraudulent 26 conduct and constitutes false claims within the meaning of Cal. Ins. Code § 1871.7(b) 27 and Sections 549 & 550(a)(6) of the California Penal Code, among other provisions. 28 Case No. 10-cv-03165 GHK (SSx) 103 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 109 of 141 Page ID #:1381 1 2 3 4 5 6 7 8 285. By reason of these payments, insurers have been damaged, and continue to be damaged, in a substantial amount. COUNT FIVE Colorado Medicaid False Claims Act, Colo. Rev. Stat. § 25.5-4-303.5, et seq. 286. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 287. This is a claim for treble damages and civil penalties under the Colorado Medicaid False Claims Act, Colo. Rev. Stat. § 25.5-4-303.5, et seq. 9 288. By virtue of the conduct described above, Defendant knowingly presented 10 or caused to be presented to the Colorado Medicaid Program false or fraudulent claims 11 for payment or approval and/or knowingly accomplished these unlawful acts by making, 12 using, or causing to be made or used a false record or statement. 13 289. Moreover by virtue of the kickbacks, misrepresentations and submissions of 14 non-reimbursable claims described above, Defendant conspired to commit violations of 15 the Colorado False Claims Act. 16 290. The Colorado Medicaid Program, unaware of the falsity or fraudulent 17 nature of the claims caused by Defendant, paid for claims that otherwise would not have 18 been allowed. 19 20 21 22 23 24 25 26 291. By reason of these payments, the Colorado Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT SIX Connecticut False Claims Act, Conn. Gen. Stat. § 17b-301b et seq. 292. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 293. This is a claim for treble damages and civil penalties under the Connecticut False Claims Act, Conn. Gen. Stat. § 17b-301b, et seq. 27 28 Case No. 10-cv-03165 GHK (SSx) 104 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 110 of 141 Page ID #:1382 1 294. By virtue of the conduct described above, Defendant knowingly caused to 2 be presented to the Delaware Medicaid Program false or fraudulent claims for the 3 improper payment or approval of prescriptions for off-label uses of Thalomid. 4 295. The Connecticut Medicaid Program, unaware of the falsity or fraudulent 5 nature of the claims caused by Defendant, paid for claims that otherwise would not have 6 been allowed. 7 8 9 10 11 12 13 14 296. By reason of these payments, the Connecticut Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT SEVEN Delaware False Claims Act, Del. Code Ann. Tit. 6, § 1201 et seq. 297. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 298. This is a claim for treble damages and civil penalties under the Delaware False Claims Act. Del Code Ann. tit. 6, § 1201 et seq. 15 299. By virtue of the conduct described above, Defendant knowingly caused to 16 be presented to the Delaware Medicaid Program false or fraudulent claims for the 17 improper payment or approval of prescriptions for off-label uses of Thalomid. 18 300. The Delaware Medicaid Program, unaware of the falsity or fraudulent 19 nature of the claims caused by Defendant, paid for claims that otherwise would not have 20 been allowed. 21 22 23 24 25 26 27 28 301. By reason of these payments, the Delaware Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT EIGHT Florida False Claims Act, Fla. Stat. Ann. § 68.081 et seq. 302. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 303. This is a claim for treble damages and civil penalties under the Florida False - Claims Act. Fla. Stat. Ann. § 68.081 et seq. Case No. 10-cv-03165 GHK (SSx) 105 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 111 of 141 Page ID #:1383 1 304. By virtue of, the conduct described above, Defendant knowingly caused to 2 be presented to the Florida Medicaid Program false or fraudulent claims for the improper 3 payment or approval of prescriptions for off-label uses of Thalomid and Revlimid. 4 305. The Florida Medicaid Program, unaware of the falsity or fraudulent nature 5 of the claims caused by Defendant, paid for claims that otherwise would not have been 6 allowed. 7 8 306. By reason of these payments, the Florida Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. 9 COUNT NINE Georgia False Medicaid Claims Act, O.C.G.A. § 49-4-168 et seq. 10 11 12 13 14 307. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 308. This is a claim for treble damages and civil penalties under the Georgia False Medicaid Claims Act, O.C.G.A. § 49-4-168 et seq. 15 309. By virtue of, the conduct described above, Defendant knowingly caused to 16 be presented to the Georgia Medicaid Program false or fraudulent claims for the 17 improper payment or approval of prescriptions for off-label uses of Thalomid and 18 Revlimid. 19 310. The Georgia Medicaid Program, unaware of the falsity or fraudulent nature 20 of the claims caused by Defendant, paid for claims that otherwise would not have been 21 allowed. 22 23 24 25 26 27 311. By reason of these payments, the Georgia Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT TEN Hawaii False Claims Act, Haw. Rev. Stat. § 661-22 et seq. 312. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 28 Case No. 10-cv-03165 GHK (SSx) 106 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 112 of 141 Page ID #:1384 1 2 313. This is a claim for treble damages and civil penalties under the Hawaii False Claims Act. Haw. Rev. Stat. § 661-22 et seq. 3 314. By virtue of the conduct described above, Defendant knowingly caused to 4 be presented to the Hawaii Medicaid Program false or fraudulent claims for the improper 5 payment or approval of prescriptions for off-label uses of Thalomid and Revlimid. 6 315. The Hawaii Medicaid Program, unaware of the falsity or fraudulent nature 7 of the claims caused by Defendant, paid for claims that otherwise would not have been 8 allowed. 9 10 316. By reason of these payments, the Hawaii Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. 11 COUNT ELEVEN Illinois Whistleblower Reward and Protection Act, 740 III. Comp. Stat. 175/1 et seq. 12 13 14 15 16 317. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 318. This is a claim for treble damages and civil penalties under the Illinois Whistleblower Reward and Protection Act. 740 111. Comp. Stat. 175/1 et seq. 17 319. By virtue of the conduct described above, Defendant knowingly caused to 18 be presented to the Illinois Medicaid Program false or fraudulent claims for the improper 19 payment or approval of prescriptions for off-label uses of Thalomid and Revlimid. 20 320. The Illinois Medicaid Program, unaware of the falsity or fraudulent nature 21 of the claims caused by Defendant, paid for claims that otherwise would not have been 22 allowed. 23 24 25 26 27 28 321. By reason of these payments, the Illinois Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT TWELVE Indiana False Claims and Whistleblower Protection Act, Indiana Code § 5-11-5.5 322. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. Case No. 10-cv-03165 GHK (SSx) 107 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 113 of 141 Page ID #:1385 1 2 323. This is a claim for treble damages and civil penalties under the Indiana False Claims and Whistleblower Protection Act, Indiana Code § 5-11-5.5. 3 324. By virtue of the conduct described above, Defendant knowingly caused to 4 be presented to the Indiana Medicaid Program false or fraudulent claims for the 5 improper payment or approval of prescriptions for off-label uses of Thalomid and 6 Revlimid. 7 325. The Indiana Medicaid Program, unaware of the falsity or fraudulent nature 8 of the claims caused by Defendant, paid for claims that otherwise would not have been 9 allowed. 10 11 12 13 14 15 16 17 326. By reason of these payments, the Indiana Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT THIRTEEN Maryland False Health Claims Act of 2010, Md. Code Ann. § 2-601 et seq. 327. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 328. This is a claim for treble damages and civil penalties under the Maryland False Health Claims Act, Md. Code Ann. § 2-601 et seq. 18 329. By virtue of the conduct described above, Defendant knowingly presented 19 or caused to be presented to the Maryland Medicaid Program false or fraudulent claims 20 for payment or approval and/or knowingly accomplished these unlawful acts by making, 21 using, or causing to be made or used a false record or statement. 22 330. Moreover by virtue of the kickbacks, misrepresentations and submissions of 23 non-reimbursable claims described above, Defendant conspired to commit violations of 24 the Maryland False Health Claims Act. 25 331. The Maryland Medicaid Program, unaware of the falsity or fraudulent 26 nature of the claims caused by Defendant, paid for claims that otherwise would not have 27 been allowed. 28 Case No. 10-cv-03165 GHK (SSx) 108 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 114 of 141 Page ID #:1386 1 2 332. By reason of these payments, the Maryland Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. 3 COUNT FOURTEEN Louisiana Medical Assistance Programs Integrity Law, La. Rev. Stat. Ann. § 46:439.1 et seq. 4 5 6 7 8 333. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 334. This is a claim for treble damages and civil penalties under the Louisiana Medical Assistance Programs Integrity Law. La. Rev. Stat. Ann. § 46:439.1 et seq. 9 335. By virtue of the conduct described above, Defendant knowingly caused to 10 be presented to the Louisiana Medicaid Program false or fraudulent claims for the 11 improper payment or approval of prescriptions for off label uses of Thalomid and 12 Revlimid. 13 336. The Louisiana Medicaid Program, unaware of the falsity or fraudulent 14 nature of the claims caused by Defendant, paid for claims that otherwise would not have 15 been allowed. 16 17 18 19 20 21 22 23 337. By reason of these payments, the Louisiana Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT FIFTEEN Massachusetts False Claims Act, Mass. Ann. Laws Ch. 12, § 5(A)-(0) 338. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 339. This is a claim for treble damages and civil penalties under the Massachusetts False Claims Act. Mass. Ann. Laws ch. 12, § 5(A)-(0). 24 340. By virtue of the conduct described above, Defendant knowingly caused to 25 be presented to the Massachusetts Medicaid Program false or fraudulent claims for the 26 improper payment or approval of prescriptions for off-label uses of Thalomid and 27 Revlimid. 28 Case No. 10-cv-03165 GHK (SSx) 109 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 115 of 141 Page ID #:1387 1 341. The Massachusetts Medicaid Program, unaware of the falsity or fraudulent 2 nature of the claims caused by Defendant, paid for claims that otherwise would not have 3 been allowed. 4 5 342. By reason of these payments, the Massachusetts Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. 6 COUNT SIXTEEN Michigan Medicaid False Claims Act, MCLS § 400.601 et seq. 7 8 9 10 11 343. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 344. This is a claim for treble damages and civil penalties under the Michigan Medicaid False Claims Act, MCLS § 400.601 et seq. 12 345. By virtue of the conduct described above, Defendant knowingly caused to 13 be presented to the Michigan Medicaid Program false or fraudulent claims for the 14 improper payment or approval of prescriptions for off-label uses of Thalomid and 15 Revlimid. 16 346. The Michigan Medicaid Program, unaware of the falsity or fraudulent 17 nature of the claims caused by Defendant, paid for claims that otherwise would not have 18 been allowed. 19 20 21 22 23 24 25 26 347. By reason of these payments, the Michigan Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT SEVENTEEN Minnesota False Claims Act Minn. State Minn. Stat. § 15C.01 et seq. 348. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 349. This is a claim for treble damages and civil penalties under the Minnesota False Claims Act Minn. Stat. § 15C.01 et seq. 27 350. By virtue of the conduct described above, Defendant knowingly presented 28 or caused to be presented to the Minnesota Medicaid Program false or fraudulent claims Case No. 10-cv-03165 GHK (SSx) 110 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 116 of 141 Page ID #:1388 1 for payment or approval and/or knowingly accomplished these unlawful acts by making, 2 using, or causing to be made or used a false record or statement. 3 4 351. Moreover by virtue of the conduct described above, Defendant conspired to commit violations of the Minnesota False Claims Act. 5 352. The Minnesota Medicaid Program, unaware of the falsity or fraudulent 6 nature of the claims caused by the Defendant, paid for claims that otherwise would not 7 have been allowed. 8 9 353. By reason of these payments, the Minnesota Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. 10 COUNT EIGHTEEN Montana False Claims Act, Mont. Code Anno § 17-8-401 et seq. 11 12 13 14 15 354. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 355. This is a claim for treble damages and civil penalties under the Montana False Claims Act. Mont. Code Anno. § 17-8-401 et seq. 16 356. By virtue of the conduct described above, Defendant knowingly presented 17 or caused to be presented to the Montana Medicaid Program false or fraudulent claims 18 for payment or approval and/or knowingly accomplished these unlawful acts by making, 19 using, or causing to be made or used a false record or statement. 20 357. The Montana Medicaid Program, unaware of the falsity or fraudulent nature 21 of the claims caused by Defendant, paid for claims that otherwise would not have been 22 allowed. 23 24 25 26 27 28 358. By reason of these payments, the Montana Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT NINETEEN Nevada False Claims Act, Nev. Rev. Stat. § 357.010 et seq. 359. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. Case No. 10-cv-03165 GHK (SSx) 111 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 117 of 141 Page ID #:1389 1 2 360. This is a claim for treble damages and civil penalties under the Nevada False Claims Act. Nev. Rev. Stat. § 357.010 et seq. 3 361. By virtue of the conduct described above, Defendant knowingly caused to 4 be presented to the Nevada Medicaid Program false or fraudulent claims for the 5 improper payment or approval of prescriptions for off-label uses of Thalomid and 6 Revlimid. 7 362. The Nevada Medicaid Program, unaware of the falsity or fraudulent nature 8 of the claims caused by Defendant, paid for claims that otherwise would not have been 9 allowed. 10 11 363. By reason of these payments, the Nevada Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. 12 COUNT TWENTY New Hampshire Medicaid Fraud and False Claims, N.H. Rev. Stat. Ann. § 167:61 et seq. 13 14 15 364. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 16 365. This is a claim for treble damages and civil penalties under the New 17 Hampshire Medicaid Fraud and False Claims Law, N.H. Rev. Stat. Ann. § 167:61, et 18 seq. 19 366. By virtue of the conduct described above, Defendant knowingly caused to 20 be presented to the New Hampshire Medicaid Program false or fraudulent claims for the 21 improper payment or approval of prescriptions for off-label uses of Thalomid and 22 Revlimid. 23 367. The New Hampshire Medicaid Program, unaware of the falsity or 24 fraudulent nature of the claims caused by Defendant, paid for claims that otherwise 25 would not have been allowed. 26 27 368. By reason of these payments, the New Hampshire Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. 28 Case No. 10-cv-03165 GHK (SSx) 112 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 118 of 141 Page ID #:1390 1 COUNT TWENTY-ONE New Jersey False Claims Act, N.J. Stat. § 2A:32C-1 et seq. 2 3 4 5 6 369. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 370. This is a claim for treble damages and civil penalties under the New Jersey False Claims Act. N.J. Stat. § 2A:32C-1 et seq. 7 371. By virtue of the conduct described above, Defendant knowingly presented 8 or caused to be presented to the New Jersey Medicaid Program false or fraudulent claims 9 for payment or approval and/or knowingly accomplished these unlawful acts by making, 10 using, or causing to be made or used a false record or statement. 11 372. The New Jersey Medicaid Program, unaware of the falsity or fraudulent 12 nature of the claims caused by Defendant, paid for claims that otherwise would not have 13 been allowed. 14 15 16 17 18 19 20 21 373. By reason of these payments, the New Jersey Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT TWENTY-TWO New Mexico Medicaid False Claims Act, N.M. Stat. Ann. § 27-14-1 et seq. 374. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 375. This is a claim for treble damages and civil penalties under the New Mexico Medicaid False Claims Act. N.M. Stat. Ann. § 27-14-1 et seq. 22 376. By virtue of the conduct described above, Defendant knowingly caused to 23 be presented to the New Mexico Medicaid Program false or fraudulent claims for the 24 improper payment or approval of prescriptions for off-label uses of Thalomid and 25 Revlimid. 26 377. The New Mexico Medicaid Program, unaware of the falsity or fraudulent 27 nature of the claims caused by Defendant, paid for claims that otherwise would not have 28 been allowed. Case No. 10-cv-03165 GHK (SSx) 113 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 119 of 141 Page ID #:1391 1 2 378. By reason of these payments, the New Mexico Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. 3 COUNT TWENTY-THREE New York False Claims Act, N.Y. CLS St. Fin. § 186 et seq. 4 5 6 7 8 379. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 380. This is a claim for treble damages and civil penalties under the New York False Claims Act, N.Y. CLS St. Fin. § 186 et seq. 9 381. By virtue of the conduct described above, Defendant knowingly caused to 10 be presented to the New York Medicaid Program false or fraudulent claims for the 11 improper payment or approval of prescriptions for off-label uses of Thalomid and 12 Revlimid. 13 382. The New York Medicaid Program, unaware of the falsity or fraudulent 14 nature of the claims caused by Defendant, paid for claims that otherwise would not have 15 been allowed. 16 17 18 19 20 21 22 23 383. By reason of these payments, the New York Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT TWENTY-FOUR North Carolina False Claims Act, N.C. Gen. Stat. § 1-605 et seq. 384. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 385. This is a claim for treble damages and civil penalties under the North Carolina False Claims Act, N.C. Gen. Stat. § 1-605 et seq. 24 386. By virtue of the conduct described above, Defendant knowingly presented 25 or caused to be presented to the North Carolina Medicaid program for false or fraudulent 26 claims for payment or approval and/or knowingly accomplished these unlawful acts by 27 making, using, or causing to be made or used a false record or statement. 28 Case No. 10-cv-03165 GHK (SSx) 114 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 120 of 141 Page ID #:1392 1 387. The North Carolina Medicaid Program, unaware of the falsity or fraudulent 2 nature of the claims caused by Defendant, paid for claims that otherwise would not have 3 been allowed. 4 5 6 7 8 9 10 11 388. By reason of these payments, the North Carolina Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT TWENTY-FIVE Oklahoma Medicaid False Claims Act, 63 Okl. St. §5053 et seq. 389. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 390. This is a claim for treble damages and civil penalties under the Oklahoma Medicaid False Claims Act. 63 Okl. St. § 5053 et seq. 12 391. By virtue of the conduct described above, Defendant knowingly presented 13 or caused to be presented to the Oklahoma Medicaid Program false or fraudulent claims 14 for payment or approval and/or knowingly accomplished these unlawful acts by making, 15 using, or causing to be made or used a false record or statement. 16 392. The Oklahoma Medicaid Program, unaware of the falsity or fraudulent 17 nature of the claims caused by Defendant, paid for claims that otherwise would not have 18 been allowed. 19 20 21 22 23 24 25 26 393. By reason of these payments, the Oklahoma Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT TWENTY-SIX Rhode Island False Claims Act, R.I. Gen. Laws §9-1.1-1 et seq. 394. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 395. This is a claim for treble damages and civil penalties under the Rhode Island False Claims Act. R.I. Gen. Laws § 9-1.1-1 et seq. 27 396. By virtue of the conduct described above, Defendant knowingly presented 28 or caused to be presented to the Rhode Island Medicaid Program false or fraudulent Case No. 10-cv-03165 GHK (SSx) 115 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 121 of 141 Page ID #:1393 1 claims for payment or approval and/or knowingly accomplished these unlawful acts by 2 making, using, or causing to be made or used a false record or statement. 3 397. The Rhode Island Medicaid Program, unaware of the falsity or fraudulent 4 nature of the claims caused by Defendant, paid for claims that otherwise would not have 5 been allowed. 6 7 8 9 10 11 398. By reason of these payments, the Rhode Island Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT TWENTY-SEVEN Tennessee Medicaid False Claims Act, Tenn. Code Ann. § 71-5-181 et seq. and Tennessee False Claims Act, Tenn. Code Ann. § 4-18-101 et seq. 399. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 12 400. This is a claim for treble damages and civil penalties under the Tennessee 13 Medicaid False Claims Act, and the Tennessee False Claims Act. Tenn. Code Ann. § 71- 14 5-181 et seq.; Tenn. Code Ann. § 4-18-101 et seq. 15 401. By virtue of the conduct described above, Defendant knowingly caused to 16 be presented to the Tennessee Medicaid Program false or fraudulent claims for the 17 improper payment or approval of prescriptions for off-label uses of Thalomid and 18 Revlimid. 19 402. The Tennessee Medicaid Program, unaware of the falsity or fraudulent 20 nature of the claims caused by Defendant, paid for claims that otherwise would not have 21 been allowed. 22 23 24 25 26 27 403. By reason of these payments, the Tennessee Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT TWENTY-EIGHT Texas Medicaid Fraud Prevention Act, Tex. Hum. Res. Code Ann. § 36.001 et seq. 404. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 28 Case No. 10-cv-03165 GHK (SSx) 116 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 122 of 141 Page ID #:1394 1 2 405. This is a claim for treble damages and civil penalties under the Texas Medicaid Fraud Prevention Act. Tex. Hum. Res. Code Ann. § 36.001 et seq. 3 406. By virtue of the conduct described above, Defendant knowingly caused to 4 be presented to the Texas Medicaid Program false or fraudulent claims for the improper 5 payment or approval of prescriptions for off-label uses of Thalomid and Revlimid. 6 407. The Texas Medicaid Program, unaware of the falsity or fraudulent nature of 7 the claims caused by Defendant, paid for claims that otherwise would not have been 8 allowed. 9 10 11 12 13 14 15 16 408. By reason of these payments, the Texas Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT TWENTY-NINE Virginia Fraud Against Taxpayers Act, Va. Code Ann. §8.01-216 et seq. 409. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 410. This is a claim for treble damages and civil penalties under the Virginia Fraud Against Taxpayers Act. Va. Code Ann. §8.01-21.6 et seq. 17 411. By virtue of the conduct described above, Defendant knowingly caused to 18 be presented to the Virginia Medicaid Program false or fraudulent claims for the 19 improper payment or approval of prescriptions for off-label uses of Thalomid and 20 Revlimid. 21 412. The Virginia Medicaid Program, unaware of the falsity or fraudulent nature 22 of the claims caused by Defendant, paid for claims that otherwise would not have been 23 allowed. 24 25 413. By reason of these payments, the Virginia Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. 26 27 28 Case No. 10-cv-03165 GHK (SSx) 117 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 123 of 141 Page ID #:1395 1 COUNT THIRTY Washington Medicaid Fraud False Claims Act, Rev. Code Wash. § 48.80.010 et seq. 2 3 4 5 6 414. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 415. This is a claim for treble damages and civil penalties under the Washington Medicaid Fraud False Claims Act, Rev. Code Wash. § 48.80.010 et seq. 7 416. By virtue of the conduct described above, Defendant knowingly presented 8 or caused to be presented to the Washington Medicaid Program false or fraudulent 9 claims for payment or approval and/or knowingly accomplished these unlawful acts by 10 making, using, or causing to be made or used a false record or statement. 11 417. Moreover by virtue of the kickbacks, misrepresentations and submissions of 12 non-reimbursable claims described above, Defendant conspired to commit violations of 13 the Washington Medicaid Fraud False Claims Act. 14 418. The Washington Medicaid Program, unaware of the falsity or fraudulent 15 nature of the claims caused by Defendant, paid for claims that otherwise would not have 16 been allowed. 17 18 19 20 21 22 23 24 419. By reason of these payments, the Washington Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT THIRTY-ONE Wisconsin False Claims Act, Wis. Stat. § 20.931 et seq. 420. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 421. This is a claim for treble damages and civil penalties under the Wisconsin False Claims Act. Wis. Stat. § 20.931 et seq. 25 422. By virtue of the conduct described above, Defendant knowingly presented 26 or caused to be presented to the Wisconsin Medicaid Program false or fraudulent claims 27 for payment or approval and/or knowingly accomplished these unlawful acts by making, 28 using, or causing to be made or used a false record or statement. Case No. 10-cv-03165 GHK (SSx) 118 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 124 of 141 Page ID #:1396 1 423. The Wisconsin Medicaid Program, unaware of the falsity or fraudulent 2 nature of the claims caused by Defendant, paid for claims that otherwise would not have 3 been allowed. 4 5 6 7 8 9 10 11 424. By reason of these payments, the Wisconsin Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT THIRTY-TWO District of Columbia False Claims Act, D.C. Code § 2-308.03 et seq. 425. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 426. This is a claim for treble damages and civil penalties under the District of Columbia False Claims Act. D.C. Code § 2-308.03 et seq. 12 427. By virtue of the conduct described above, Defendant knowingly caused to 13 be presented to the District of Columbia Medicaid Program false or fraudulent claims for 14 the improper payment or approval of prescriptions for off-label uses of Thalomid and 15 Revlimid. 16 428. The District of Columbia Medicaid Program, unaware of the falsity or 17 fraudulent nature of the claims caused by Defendant, paid for claims that otherwise 18 would not have been allowed. 19 20 21 22 23 24 25 26 429. By reason of these payments, the District of Columbia Medicaid Program has been damaged, and continues to be damaged, in a substantial amount. COUNT THIRTY-THREE City of Chicago False Claims Act, Chicago Mun. Code Chapter 1-22 et seq. 430. Relator re-alleges and incorporates by reference the allegations contained in the preceding paragraphs of this Complaint. 431. This is a claim for treble damages and civil penalties under the City of Chicago False Claims Act, Chicago Municipal Code Chapter 1-22, et seq. 27 28 Case No. 10-cv-03165 GHK (SSx) 119 THIRD AMENDED COMPLAINT Case 2:10-cv-03165-GHK-SS Document 72 Filed 02/05/14 Page 125 of 141 Page ID #:1397 1 432. By virtue of the conduct described above, Defendant knowingly caused to 2 be presented to the City of Chicago false or fraudulent claims for the improper payment 3 or approval of prescriptions for off-label uses of Thalomid and Revlimid. 4 433. The City of Chicago, unaware of the falsity or fraudulent nature of the 5 claims caused by Defendant, paid for claims that otherwise would not have been 6 allowed. 7 8 9 10 11 434. By reason of these payments, the City of Chicago has been damaged, and continues to be damaged, in a substantial amount. WHEREFORE, Relator requests that judgment be entered against Defendant, ordering that: (i) Defendant ceases and desists from violating the False Claims Act, 31 12 U.S.C. § 3729, et seq., the State False Claims Acts, and the California Insurance Frauds 13 Prevention Act; 14 (ii) Defendant pays not less than $5,500 and not more than $11,000 for each 15 violation of 31 U.S.C. § 3729, plus three times the amount of damages the United States 16 has sustained because of Defendant’s actions, plus the appropriate amount to the States 17 under similar provisions of the state false claims acts; 18 (iii) Defendant pays $10,000 for each and every fraudulent claim Defendant 19 presented or caused to be presented to an insurance company, plus three times the 20 amount of damages the insurance companies sustained because of Defendant’s actions 21 pursuant to the California Insurance Frauds Prevention Act; 22 (iv) The Relator be awarded the maximum “relator’s share” allowed pursuant to 23 31 U.S.C. § 3730(d) and similar provisions of the state false claims acts and the 24 California Insurance Frauds Prevention Act; 25 (v) The Relator be awarded all costs of this action, including attorneys’ fees 26 and costs pursuant to 31 U.S.C. § 3730(d) and similar provisions of the State False 27 Claims Acts the California Insurance Frauds Prevention Act; 28 Case No. 10-cv-03165 GHK (SSx) 120 THIRD AMENDED COMPLAINT U.) r--L 45>> l--iase Document 72 Filed 02/05/14 Page 126 of 141 Page ID #21398 (vi) Defendant be enjoined from concealing, removing, encumbering or disposing of assets which may be required to pay the civil monetary penalties imposed by the Court; (vii) wrongful conduct; and The United States, the States, and the Relator recover such other relief as Defendant disgorges all sums by which it has been enriched unjustly by its the Court deems just and proper. Dated: February 5, 2014 GRANT EISENHOFER P.A Reuben A. Guttman Traci L. Buschner David T. Fischer Jay W. Eisenhofer Attorneys for Plaintiff Relator BEVERLY BROWN By: Case No. lO--cv--03 165 GHK 121 THIRD AMENDED COMPLAINT ase Document 72 Filed 02/05/14 Page 127 of 141 Page ID demands atrial by jury. Dated: February 5, 2014 Case No. 10-cv-03165 GHK (SSX) #21399 REQUEST FOR TRLAL BY JURY Pursuant to Rule 38 of the Federal Rules of Civil Procedure, Relator hereby GMNT EISENHOFER P.A Reuben A. Guttman Traci L. Buschner David T. Fischer Jay W. Eisenhofer Attorneys for Plaintiff -- Relator BEVERLY BROWN 122 THERD AMENDED COIWPLATNT Case Document 72 Filed 02/05/14 Page 128 of 141 Page ID #21400 Case Fwagreomegsefomvl-1 Page ID 1401 2008 1 12: 44454451 Prepublish ed online September 17, 2008; Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure Michael Wang, Meletios A. Dimopoulos, Christine Chen, M. Teresa Cibeira, Michel Attal, Andrew Spencer, 8. Vincent Rajkumar, Zhinuan Yu, Marta Jerome B. Zeldis, Robert D. Knight and Donna M. Weber Updated information and services can be found at: Articles on similar topics can be found in the following Blood collections Clinical Trials and Observations (3768 articles) Free Research Articles (1929 articles) Neoplasia (4212 articles) information about reproducing this article in parts or in its entirety ma be found online at: repub__requests information about ordering reprints may be found oniine at: information about subscriptions and ASH membership may be found online at: Blood (print 0006-4971, online 1528-0020), is published weekly by the American Society of Hematology, 2021 St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all fights reserved. Case Document 72 Filed 02/05/14 Page 130 of 141 Page ID CLINICAL AND OBSERVATIONS #21402 Lenalidornide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure Michael Wang,' Meletios A. Dimopoulosfi Christine Chen? M. Teresa Cibeira,' Michel Attal,-" Andrew Spencer," 8. Vincent Raikumar,7 Zhinuan Yo," Marta Jerome B. Zeldis,3 Robert D. Knight," and Donna M. Weber' 'Departmental and Myeloma, M. D. Anderson Cancer Center, Houston, 'Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece; 3Department of Medicine. Princess Margaret Hospital, Toronto, 'Hematology Department, institute of Hematology and Oncology, Hospital Clinic, lnstitut d'lnvestigaclons Biom?diques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona. Spain; 5Divlsion oi Hematology, Centre Hospitalier Universit? de Purpan, Toulouse. France; "Department oi Malignant Hematology and Stem Cell Transplantation Service, The Alfred Hospital, Melbourne. Australia: 7Mayo Clinic Cancer Center, Rochester, and Bcelgane, Summit. NJ This analysis assessed the efficacy and safety of lenalidomide dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. 01 704 patients, 39% were thalidomide exposed. Thalidomide- exposed patients had more prior lines of therapy and longer duration oi' myeloma than thalidomide-naive patients. Lenalido- mide dexamethasone led to higher overall response rate (ORR), longertimeto progres- sion (TTP), and progression-free survival (PFS) versus placebo dexarnethasone despite prior thalidomide exposure. Among lenalidomide dexamethasone-treated pa- tients, OFIFI was higher in thalidomide-naive versus thalidomide-exposed patients (P .04). with longer median TTP (P: .04) and PFS (P .02). Likewise for dexametha- sonealone-treated patients (P .03 for ORR, P: .03 for P: .06 for PFS). Prior thalidomide did not affect survival in lenalidomide dexamethasone-treated patients (36.1 vs 33.3 months, .05). Thalidomide-naive and thalidomide- exposed patients had similar toxicities. Lenalidomide dexamelhasone resulted in higher rates of venous thromboemboiism, myelosuppression, and infections versus placebo dexarnethasone, independent of prior thalidomide exposure. Lenalido- mide dexamethasone was superior to placebo dexamethasone, independent of prior thalidomide exposure. Although prior thalidomide may have contributed to infe- rior TTP and PFS compared with thalido- mide-nalve patients, these parameters remained superior compared with placebo dexarnethasone; similar benefits com- pared with plaoebo dexamethasone were not evident for thalidomide-exposed pa- tients in terms of overall survival. studies were registered at gov under NCT00056160 and NOT 00424047. (Blood. Introduction Despite advances in the tteaunent of multiple myeloma (MM), a disease characterized by the accumulation of clonal plasma cells in the bone marrow, the disease remains incurable. With the advent of novel therapies, the median survival of relapsed patients has been improved from about i to 2 years after relapse.' It is estimated that about 20 000 people (it 000 men and 9 000 women) will be diagnosed with MM, and 1 000 will die because of the disease in the United States'. in 2008.2 Patients relapsing after 2000 had a median survival of 24 months, which was a clear improvement compared with those relapsing before 2000, indicating the benefit of new treatment options? Nevertheless, novel agents and their rational combinations are needed. In the mid~] 9905, it new class of immunomodulalory drugs was designed and using the structural backbone of thalidomide as the tem- plate- The intention was to create analogs with enhanced efficacy and reduced toxicity relative to their parent compouncL"5 Lcnalidomidc (Revlimid; Celgcne, Summit", NJ) is an oral derivative of thalidomide that has proven activity against MM in preclinical and clinical stud- Whereas the immunomodulatory effects and in vivo antitumor activity of lcnalidomide are similar to thalidomide, improved potency (evidenced by a greater ability to stimulate T--ccli proliferation, interleu- kin-2 and interferon-y production, and to inhibit tumor cell growth) and reduced toxicity (reduced somnolence, constipation, and peripheral ncuropalhy; no evidence of tcratogcnicity or in preclinical models) favor However, i.t must be noted that not commonly observed with thalidomide, is often observed with Recently, lcnalidomide plus dcxametha- sent: was shown to be also highly active in newly diagnosed MM, lending in durable responses and a low progression rate and mortality." In 2 prospective, randomized, double-blind, p.lacebo--control.ied phase 3 clinical trials (MM-009 and it was shown that icnalidomidc plus dcxamcthasonc induced significantly higher rates of overall rc- sponsc (OR) and complete response (CR), as well as longer time to progression (TFP), and overall survival (03), compared with placebo plus dexznnethasonc in patients with relapsed or refractory Since lcnalidomide is a derivative of thalidomide, there has been concern about possible resistance to lcnalidomide in patients who had relapsed after, or who were refractory to, treatment with thalidomide. Preliminary data from early phase 1 and 2 trials Submitted February 22. 2008: accepted July 25, 2008. online as Blood First Edition paper, September 17, 2008; D0l 141614. Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA. June 4, 2006"': the 48th Annual Meeting of the American Society of Hematology, Orlando, FL, December 10, 2006?"; and the BLOOD, 1 DECEMBER 2003 VOLUME 112. NUMBER 12 International Myeloma Workshop. Kas Island, Greece, June 26, 2007.9' The publication costs of this article were defrayed in part by page charge payment. Therelore, and solely to indicate this tact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. (C) 2008 by The American Society of Hematology 4445 Case Document 72 Filed 02/05/14 Page 131 of 141 Page ID #21403 4446 WANG et at suggested that lenalidomide alone and combined with dexametha- some produced a response in patients who had received prior The present prospective subgroup analysis of data pooled from the MM-O09 and MM-010 phase 3 clinical trials assessed the efficacy of lenalidomide plus dexamethasone in patients with prior thalidomide exposure. Methods We evaluated data from 704 patients included in the MM-009 and MM-010 trials who had relapsed or refractory MM and were not resistant to This is a secondary analysis of pooled data from 2 primary trials. Patients enrolled in these trials gave written informed consent in accordance with the Declaration of Helsinki, and an ethics committee at each study site (M. I). Anderson Cancer Center, University of Athens, Princess Margaret Hospital, University of Barcelona, Universit? de Purprm, Alfred Hospital. Mayo Clinic) approved the protocol. Patients were randomized to receive either oral lcnalidomide (25 mg/day for 2} days, every 28-day cycle) plus dexamethasonc (40 mg on days 1-4, 942, and 17-20 every 28-day cycle for 4 cycles, after the 4th cycle on days or placebo plus an identical schedule of dcxamethasone. Prophylactic antico- agulation was not recommended for the patients enrolled in the 2 trials. Patients who were dexarnethasonc resistant to more than 200 mg dexamcth- asone in a month were excluded from the 2 trials. We identified 274 patients who had received prior thalidomide treatment and 430 patients who had not been previously treated with this agent. The present analysis is a posthoc analysis, performed without prespeei- fied power calculation or adjustment for multiplicity, and is therefore considered exploratory in nature. For this analysis, patients with prior exposure to thalidomide were further categorized, according to their response to thalidomide, into the l'ollowi.ng 3 subgroups'. thalidomide- scnsitive (Tl) patients with best response of stable disease (SD) or better, who never progressed while on thalidomide; (2) thalidomidc--relapscd (T2) patients with best response of SD or better, who progressed while on thalidomide; and (3) thalidomide-rcfmetory (T3) patients who had pro- gressed while on thalidomide and never responded to prior thalidomide treatment. Patients in T1 did not progress while on thalidomide treatment, but discontinued thalidomide treatment for other reasons, such as toxicity or stem cell transplantation. For the 4] patients from the thalidomide-exposed group not included in T1, T2, or T3, response to prior thalidomide was not evaluable or was unknown. A5 previously toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 2 archivehtml). Response to treatment was assessed according to European Group for Blood and Marrow Transplanta- tion criteria"' and the Mycloma Working Group uniform response criteria," which define the following responses: CR: no M-protein detectable by immunoiixation in the serum and urine, disappearance of any soft tissue plasrnacytomas, and 5% or less plasma cells in the bone marrow; very good partial response (VGPR): 90% or more reduction in serum M-protein and urine M-protein level less than 100 mg per 24 hours; and partial response 50% or more reduction of serum M-protein and reduction in 24-hour urinary M-protein by 90% or more or less than 200 mg per 24 hours. Progressive disease was defined by any of the following: a 25% or more increase from baseline serum or urinary M-protein, which must also be an absolute increase of at least 500 mg/dL in scnun or 200 mg per 24 hours in urine; new or increased size of bone lesions or plasmacyto-- mas; or development of (serum calcium 2.875 [l 1.5 Tl'? was measured from randomization to the date of the first assessment showing disease progression. Patients who died or discon- tinued the study without evidence of disease progression were censored at the last evaluation for assessment of TFP. Progression-l"rce survival (PPS) was measured from randomization to the date of the first assessment showing disease progression or death during treatment, whichever occurred first. Patients who were alive and discontinued the study without BLOOD, 1 DECEMBER 2008 - VOLUME 112, NUMBER 12 evidence of disease progression were censored at the last evaluation for assessment of PFS. OS was calculated as the time from randomization until death from any cause, or censored at the last follow-up visit. Followup data on OS were obtained up to January 2007, for a median follow-up duration of 31.3 months. Data on OR, and PFS were assessed up to unblinding, which occurred in June 2005 for study MM-009 and August 2005 for study MM-010, for a median follow-up duration of 17.5 months. Differences in OR rates between treatment groups were analyzed using continuity- correctcd Pearson chi square tests. Timevto-event variables with censoring, including PPS, OS, and response duration, were estimated by Kaplan-Meier methods. Two-sided log-rank tests were used to compare survivorship functions between treatment groups for PFS, OS, and response duration. Results Patient characteristics The prior thalidomide-exposed patients and thalidomide-naive patients were similar with regard to age; Bymicroglobulin, hemo- globin, serum M-protein, and creatinine levels; and history of previous transplantation (Table 1). Patients previously treated with thalidomide had significantly more prior lines of therapy (P .05) and a longer time since diagnosis (P .05) compared with patients who were thalidomide naive (Table 1). The thalidomide-exposed patients were also more likely to have received prior dexametha- sone compared with the thalidomide-naive group (P .001). Although numbers were small, :1 nonsignificant trend was observed for prior hortczomib treatment (10% vs Within the lcnalidomide plus dexamethasouc treatment group, patients previously treated with thalidomide had a lower absolute neutro- phil count (P .05) compared with patients who were thalidomide naive (Table 1). Outcomes For patients treated with lenalidomide plus dexamethasone, the OR rate was higher in the thalidomide-naive than in the thalidornide-exposed group of patients (65% vs 54%, .04; Table 2), but response duration was not different (median of 16.2 months vs 13.4 months, .41; Table 2). The same difference in OR rate was seen for patients treated with dexamcthasone alone (28% vs 14%, respectively; .003). In T2 and T3 subgroups, despite the small sample sizes and therefore limited statistical power, treatment with lenalidomidc plus dexamethasone resulted in a significantly higher OR rate than dexamethasone alone (P .05; Tables Even the group categorized as being refractory to thalidomide (T3) benefited from lenalidomide plus dexamethasone treatment with a higher OR rate compared with dexarnethasone alone (P 2 .042; Table 3). Treatment with lenalidomide plus dexamethasone led to a longer duration of response than treatment with dexatnethasone alone in thalidomide-naive patients and in those who had received prior thalidomide (P .01 for both comparisons; Table 2). Dura- tion of response was similar among patients in these thalidomide- relapsed (T2) and thalidomide-refractory (T3) subgroups treated with lenalidomide plus dexamethasone (T2 vs T3: .88). Lenalidomide plus dexamethasone was significantly more effective than dcxamethasone alone in prolonging TTP and PPS in all subgroups (Tables 2,3; Figure 1). The group categorized as being refractory to thalidomide (T3) benefited from treatment with lenaliclomide plus dcxamethasone, with prolonged and Case Document 72 Filed 02/05/14 Page 132 of 141 Page ID 1404 BLOOD, 1 DECEMBER 2008 - VOLUME 112, NUMBER 12 LENIDEX EFFICACY REGARDLESS OF 4-447 Table 1. Characteristics oi' study patients (N 704) No prior exposure to thalidomide, 430 Prior exposure to thalidomide. 274 Characteristic Ler1IDex, a 226 Plaoebolnex, 204 Lenmex, 127 Placeboloex, 147 Median age, 64 64 63 62 Median prior lines of therapy, no. 24: 2? 31: 3? Median time since diagnosis, 2.81 2.95 4.3? Median baseline ECOG score 1 'l 0 1 Mean Bgmicmglobutin. mgIl_ (SD) 4.1 (2.7) 4.2 (3.1) 4.8 (4-6) 4.0 (2.6) Mean hemoglobin, g/L (SD) 1.16 (0.17) 1.18 (0.18) 1.18 (0.21) 1.17 (0.19) Mean serum M-protein. g/dL (SD) 2.6 (1.6) 2.6 (1.7) 2.6 (1.9) 2.7 (1.6) Mean ANGPS. x10?lL (SD) 3.4 (1 .3): 3.5 (1.7) 2.9 (1.3): 3.2 (1.6) Mean oroatinino, p.M (SD) 1.0 (0.4) 1.0 (0.4) 1.1 (0.4) 1.0 (0.4) Previous traneplantatlon(sPrior clexamethasone, 65 59 89 84 Prior bortozornib. 7 6 9 10 Prior vincristinedisease statusMedian duration of prior thalidomide 10 10 treatment, mo' Median time since last thalidomide NIA NIA 7 5 exposure, mo) ANC-PS indicates absotute noutrophil count--phosphotidyl serine; Dex, dexamothasone; ECOG. Eastern Cooperative Oncology Group; Len, lenalidomide; MM. multiple rnyelomag not applicable; NS. not significant; SD, standard deviation. 'Data missing tor 3 patients receiving tenatidomide plus dexamethasone and 2 patients receiving dexamethasono alone. '(Data missing for 2 patients receiving lenatictomide plus dexamethasone and 2 patients receiving dexamethasone alone. value less than .05 for patients receiving lonatidomide plus doxamethasone is for comparison between no prior exposure vs prior exposure to thalidomide. based on Fisher exact lost. without adjustment tor multiplicity. value less than .05 tot patients receiving dexamothasone atone is for comparison between no prior exposure vs prior exposure to thaiidomide, based on Fisher exact test, without adjustment tor multiplicity. PFS cmnpared with dexamothasonc alone (P .05; Table 3). For 2). There were no differences in TTP or PFS between the thali.dom.ide- patients treated with lonalidomido plus Llcxamethasonc, and PFS mlapscd and the thalidornide-refmctory subgroups (Table 3). Results were longer in the thalidomidomaivc patients compared with the were similar for patients treated with doxamothasone alone (Table 2). thalidomide-exposed patients (median of 13.9 vs 8.4 months, .004 Per protocol, patients treated with doxamethasone alone could for median of 13.2 months vs 8.4 months, .02 for Tablo receive lenalidomide-based thempy following disease progression or Table 2. Outcomes In thalidomide-naive and patients No prior exposure to thalidomide Prior exposure to thalidomide Lenlbex, 226 Piacebolflex. 204 Lenlbex, 127 Plaoebolbex, 147 Response, Complete response 19,01 2.5 7.91 't .4 Very good partial response 19.5 4.4 13.4 0.7 Partial response 26.1 20.6 32.3 12.2 Overall response 54.61' 27.51: .001 53.51 14.3: .001 Median response duration, mo (95% ct) 15.2 (12.1 to NE) 7.9 (5.1 to 1 1.9) .o03?l 13.4 (3.5 to NE) 5.1 (3.2 to 1 1.8) .oo4ll (responders only) (n A 146) (n 55) (rr 58) (n 21) filedlan TTP, mo (95% Cl) 13.9 (1 1.1 to 18.5)1 (4.7 to .001 it 8.4 (6.7 to 11.1)? 4.6 (3.7 to 4.7): .D01l[ Progressed 43.4 77.0 59.8 79.6 Median PFS, mo (95% CI) 13.2 (10.2 to 4.7 (4.6 to 5.4) .001); 8.4 (6.5 to 10.3)? 4.6 (3.7 to 4.7) .001ll Progressed/died 43.2 60.4 62.2 80.3 Median overall survival, mo (95% CI) 36.1 (32.8 to NE) 32.0 (26.4 to NE) .041! 33.3 (25.8 to NE) 28.7 (20.6 to 36.8) NS (P .23) Died 39.8 49.5 48.8 53.7 All comparisons without adjustment for multiplicity. Cl indicates confidence interval: Dex. dexamethasone; Len. lenalidomide; NE, not estimable; NS. not significant; PFS. progressiomlree survival; and TIP, time to progression. 'Pvatue is ior comparison between lenalidomido plus dexamethasone versus ctexamethasone alone. 1'Pvatue less than .05 tor patients receiving ienalidornide plus dexamethasone is tor comparison between no prior versus prior exposure to thalidomide. tPvalue less than .05 tor patients receiving dexamothasona alone is for oornparison between no prior versus prior exposure to thalidomide. ?Probability1rom continuity-corrected Pearson chi square tests. llBase>5ided tog~rank tests for diliarancos in survival distributions. unblinding of the study (164 patients croesed over). Nevertheless. OS was significantly longer for thalidomide-naive patients originally as- signed lenalidomidc plus dexamcthasone than for those given dexameth- asonc alonc (P .04; Table 2). For thalidomide-exposed patients, there was a trend toward a longer 03 in the originally assigned lcnalidomide plus dcxamcthasone group, although it was not statistically significant (P .23; Table 2), possibly due to the smaller sample sizes of the subgroups and the confounding factors in OS analysis including crossover and other treatment options after patients discontinued the original assigned treatment. For patients receiving lcnalidomidc plus dcxamcthasone, there was no in OS between thalidomide-naive and thalidomide-exposed patients (median of 36.1 vs 33.3, .20). Twelve patients, whose only prior treatment was thal.idomidc, received lenalidotnidc plus dexamcthasonc with their only prior 100- Len/Dex no prior that Len/Dex prior that A 801 PlaoebolDex no prior that E: Placebo/Dex prior that 60Time to progression (months) Figure 1 . Kaptan-Meter plots of the tlrne to progression In the tenalidomtde plus doxamethasone and dexamethasone atone groups for patients with or without prior thalidomide exposure. The estimate of time to progression for the intent--to- treat population at the lenalidomide plus dexarr ethasone and doxamethasone alone groups. Len/Dex indicates lenalidomide plus dexamethasone; Dex, dexamelhascne; and that, thalidomide. treatment being thalidomide. Of these, 10 responded to lcnalidomide plus dcxamcthasonc, with a rate of 42%, and a median TTP of 13.6 months. For the 22 patients whose responses to prior thalidomide therapy were not evaluable and were therefore not included in the T1, T2, or T3 subgroups, 46% responded (2 PR) to lcnalidomidc plus dcxamcthasonc with a median TTP of 8.5 months, and median PFS of 8.5 months. Adverse events In thalidomide-naive patients, grade 3 or 4 deep vein thrombosis or pulmonary embolism was more common in patients treated with lcnalidornidc plus doxatnothasonc than in those who had received dcxamcthasonc alone (10% vs .05; Table 4). In thalidomide-exposed patients, the incidences of grade 3 or 4 were 15% and 3% for those treated with lenalidornidc plus dexamcthasonc and those on dexamcthasonc alone, respec- tively (P .05; Table 4). Among patients treated with lcnalido- midc plus dcxamethasone, ratcs (all grade 3 or 4) were similar. imcspective of the presence or absence of prior thalidomide treatment (15% vs 10%, respective] y; .l7; Table 4). Anticoagulation usually involves prophylactic low-molccul.ar- weight heparin (either low dose or full close), or warfarin orally with the targeted INR range between 2 and 3. Antithrombotic prophylaxis is usually with oral aspirin. We do not have data to support the choices of anticoagulation. Our data suggest to use prophylactic therapeutic anticoagulation in thalidornidc~cxposcd patients receivin lcnalidomidc plus dcxamcthasonc rather than not to use arty forms of anticoagulation. The frequencies of grade 3 or 4 ncutropcnia and thrombocytope- nia were higher for patients receiving lcnalidomidc plus dcxamcth- asortc than for those receiving dcmmethasonc alone, of prior thalidomide: treatment (Table 4). In thalidorrtidemaivc patients, the occurrence of grade 3 or 4 ncutropcnia was 32% with lcnalidomidc plus dcxamcthasonc, higher than that of dcxamethasonc alone .05). In Case Document 72 Filed 02/05/14 Page 134 of 141 Page ID #21406 BLOOD, 1 DECEMBER 2008 - VOLUME 11 2. NUMBER 12 EFFICACY FIEGARDLESS OF PRIOR THALIDOMIDE 4449 Table 4. Occurrence of grade 3 or 4 adverse events in thalidomidenaive and thalidomide-exposed patients No prior exposure to thalidomide, Prior exposure to thalidomide, Adverse event Lenluex, 226 Placebolbex, 204 Lenmex, 127 Ptacebolbex, rr 147 DWIPE 9.7' 4.4' 15.0' 2.7' Noutropenia 32.3' 4.4' 40.9' 2.1' Thrombocytopenia 10.6 5.4 17.3' 7.5' Anemia 1 0.2 5.4 1 1.8 6.9 Febrile neutropenla 2.7' 0.0' 1.6 0 infection 15.5' 7.4' 14.2 8.9 Fatigue 8.0 3.9 3.9 5.2 Gastrointestinal 5.3 2.0 2.4 1 .4 Peripheral neuropathy 0.4 0.5 3.1 0.7 All comparisons without adjustment for multiplicity. value more than .05 for all adverse events tor the comparison between no prior exposure versus prior exposure to thalidomide in patients receiving tenalidomide plus clexamatnasone. Dex indicates dexamethasone; DVT, deep-vein thrombosis: Len, lenalidomide; NS. not significant: PE. pulmonary embolism, 'Pvatue less than .05 based on comparison between Len/Dex versus Dex using Fisher exact test. thal.idomidc-exposed patients, the frequency of grade 3 or 4 ncutropcnia was 41% with lenalidornidc plus dexamethasonc, higher than that of alone .05). In patients treated with lcnalidornidc plus dcxamcthasone, the frequency of grade 3 or 4 ncutmpenia was not significantly different between thalidomidonaivc and thalidornidc-exposed patients (32% vs 41%, .05). In thalidomide-naive patients, the rate of febrile ncutropenia was 3% with lenalidomidc plus dcxamethasonc. much higher than that of alone In thalidomide-exposed pa~ ticnts, similar differences exist vs Therefore, lcnalido-- rnidc plus dexamcthasone was associated with higher frequencies of febrile ncutropcnia either in thalidornidemaivc patients or thalidomide-exposed patients. In thal.idomicl.c-naive patients, the rate of grade 3 m4 nonneutro- penic infections was 16% with lcnalidomidc plus dexamethasonc, higher than that with dcxamcthasonc alone .05). However, similar between lenalidomide plus dcxamcthasonc and dcxamethasone alone in the thalidomide-exposed group of patients did not reach statistical difference (14% vs .05). In patients treated with lcnalidornidc plus dcxarnethasoue, the frequencies of grade 3 or 4 anemia were similar for those with and without prior thalidomide exposure (P .05 for all; Table 4). In thalidomide-naive patients, the occurrence of grade 3 or 4 thrornbocytopcnia was 11% with lcnalidornidc plus dexametha-- sone, similar to that of dcxamcthasonc alone .05). In thalidomidocxposcd patients, the frequency of grade 3 or 4 thromhocytopenia was 17% with lenalidomide plus dcxamctha- sone, much higher than that of dcxamcthasonc alone .05). This was likely to be due to a combination of the rnyelosuppression by lcnalidomidc plus dcxamcthasonc and/or the impact of a greater number of prior lines of therapy and longer duration from of disease on the marrow. (Table 1). In thalidomidcmaive patients, the rate of grade 3 or 4 neuropa- thy was 0.4% with lena.l.idomidc plus dcxamethasonc, similar to that with dexamethasonc alone .05). However, in thalidom.ide-exposed patients, the rate of grade 3 or 4 neuropathy tended to be hi in patients treated with lcnalidomidc plus dcxarnethasonc, but was not significantly different from that noted i.n patients treated with alone .06, Table 4). This trend could be due to the addition of lenalidomide to therapy in patients with prior thalidomide exposure or to the greater number of prior lines of therapy and longer duration of disease prior to protocol entry (Table Dosing In patients who received prior thalidomide treatment and in those who were thalidomide naive, the median daily doses were 25 mg lenalidornidc or placebo, and 40 mg dcxamethasone in both the lcnalidomidc plus dexamethasonc and dcxamcthasone alone groups. In thal.idomidc~naive patients and those who had received prior thalidomide treatment, dose tcductions were more common in those treated with lcnalidomidc plus dcxamethasone cornpzued with asonc alone. Prior thalidomide treatment did not influence the number of patients needing a dose reduction (Table 5). Discussion Results from this posthoc subgroup analysis of data pooled from the phase 3 randomized clinical trials, and MM-010, showed that lenalidomidc plus dcxamcthasonc was more effective than dcxarnethasone alone in the treatment of patients with relapsed or refractory MM, incspectivc of prior thalidomide exposure. Further- more, lcnalidomide plus dexamethasone was active in patients who had relapsed on or had never previously responded to thalidomide. Preliminary results have shown that lcnalidomide plus dexamcth~ asonc at firsl relapse resulted in a hi gher OR rate (65% vs 58%) and Table 5. Dose reductions in thalidomide-naive and thalidomide-exposed patients No prior exposure to thalidomide l.enlDex,n :226 Median dose, Lenalidomide or placebo 25 Dexamethasone 40 Patlents with 1 or more dose reduction, no. Lenalidomide or placebo 86 (35.4) Dexamethasone 66 (29.2) Prlor exposure to thalidomide Placeboltlex, 204 Len/Dex. 127 Placebolbex(13.2) 49 (38.6) 11 (7.5) 31 (15.2) 35 (27.6) 23 (15.8) Dex indicates dexamethasone; and Len, tenalidomide. Case Document 72 Filed 02/05/14 Page 135 of 141 Page ID #21407 4450 WANG at al a longer median TTP (16.4 vs 9.5 months) than when the treatment was used later, after multiple relapses." Patients in the prior thalidomide groups were generally treated later after diagnosis (ie, in a later phase of the disease) and had received more prior therapies compared with patients not previously treated with thal.i.domide. It is interesting to note that in the small number of patients who received lenalidornide plus dexamethasone as second>> line therapy, immediately after thalidomide treatment, the combina- tion resulted in an OR (83% for the 12 patients) much higher than lenalidomide plus dexamethasone used later in the treatment, after other additional therapies. This further supports the significant role of lenalidomide plus dexamethasone as second-line treatment, regardless of prior exposure to thalidomide. Despite receiving more prior therapies and a longer duration of disease since diagnosis, 54% of patients with prior thalidomide exposure responded to lenalidomide plus dexamethasone treat- ment. Furthermore, our subgroup analysis demonstrated that even in the truly thalidomide-refractory subgroup of patients, 50% responded to lenalidomide plus dexamcthasone, with 5% achieving CR. To our knowledge, these are the highest response rates reported in patients who were resistant to thalidomide. As reported in the primary studies, a superior OR rate, TTP, and PPS after lenalidoinide plus dexamethasoue treatment compared with dexa-- methasone alone was observed, regardless of the number of prior therapies or prior exposure to thalidomide. W5 In the present analysis, the longest and PPS were observed among patients without prior thalidomide exposure who received lenalidomide plus dexamethasone. However, all the thalidomide-exposed subgroups, including those relapsed on or who were refractory to thalidomide, also benefited significantly from lenalidomide plus dexamethasone treatment. It is worth noting that the more favorable efficacy results for thalidomide- naive patients compared with thalidomide-exposed patients were not only observed in the lenalidomide plus dexarnethasonc group, but also in the dexamethasone alone group. Moreover, the l.ower efficacy of lenalidomide plus dexamethasone in tlialidomideexposed patients is likely because this is a more heavily pretreated group in general. These results indicate that although there might be some degree of cross- iesistance between thalidomide and lenalidomide, then: are still benefits for all patients regardless of prior thalidomide exposure. There was a higher incidence of DVT for the thalidomide- exposed patients who were treated with lenalidomide and dexameth- asone. We believe that all these patients should receive prophylac- tic anticoagulation. Anticoagulation usually involves prophylactic low-molecular--weight heparin (either low dose or full dose), or warfarin orally with the targeted range between 2 and 3. We do not have data from these 2 trials to support the choices of anticoagulation or antithrombotic therapy. Our data suggest to use prophylactic therapeutic anticoagulation in thalidomide-exposed patients receiving lenalidoinide plus dexamethasone or antith.rom- botic therapy rather than not to use any forms of anticoagulation or antithrombotic therapy. Currently, for patients with prior history of we use full anticoagulation as described in "Adverse events" with either full-dose low-molecular-weight heparin or warfarin with a targeted INR between 2 and 3. For patients receiving lenalidomide plus dexamethasone without prior history References BLOOD, 1 DECEMBER 2008 - VOLUME 112, NUMBER 12 of with or without prior history of thalidomide exposure, we use antithrombotic medications such as aspirin. In either thalidomide-naive or patients with rnyeloma, there were higher rates of rieutropenia with lenalidomide plus dexamethasone compared with that of dexameth- asone alone. These significantly higher rates of neutropenia were translated into higher frequencies of neutropenia fevers and severe nonneutropenia infections with lenalidomide plus dexamethasone therapy than with dexamethasone alone. The incidence of peripheral neuropathy was low in both groups of patients with and without prior thalidomide exposure, but a trend toward a higher incidence of peripheral neuropathy was observed in thalidomide-exposed patients treated with lenalidomide plus dexamethasone. These results indicate that toxicities may be increased in patients receiving lenalidomide plus dexamethasone after prior thalidomide exposure. However, it must be noted that the thalidomide-exposed patients were more heavily pretreated than the thalidomide-naive patients. In conclusion, our secondary analysis of data pooled from two phase 3 trials showed that treatment with lenalidomide plus dexamethasone was superior to dexamethasone alone in relapsed or refractory MM patients with or without prior thalidomide exposure. Prior thalidomide might have contributed to inferior TTP and PFS, without affecting OS in patients treated with lenalidornide dexamethasone or dexarnethasone alone. Acknowledgments The authors thank Dr Raymond Alexanian for his input in the analysis and the preparation of the paper. The MM-009 and MM-010 studies were funded by Celgene Corporation, Summit, editorial support for the preparation of this paper was also funded by Celgene. Authorship Contribution: M.W., M.A-D., C.C., M.T.C., M.A.., A.S., S.V.R., and D.M.W. enrolled patients; Z.Y. and M.O. analyzed results and made the figures; M.W., M.A.D.. C.C., M.A., A.S., S.V.R., Z.Y., M.O., J.B.Z., R.D.K., and D.M.W. wrote the paper; the authors were fully responsible for content and editorial decisions for this paper. Conflict-of-interest disclosure: M.W. received honoraria from Celgene and received research funding for this project from Celgene; M.A.D. received honoraria from Celgene; C.C. received honoraria and has done consultant work for Celgene; M.T.C. received honoraria for lectures from Janssen-Cilag and Pharmion; Z.Y., M.O., .B.Z., and R.D.K. are employees of Cclgene; D.M.W. received grant support and lecture fees from Celgene. All other authors declare no competing financial interests. Correspondence: Michael Wang, M. D. Anderson Cancer Center, 1515 Holcombc Blvd, Unit 429, Houston,TX 77030; e-mail: miwang@mdanderson.oxg. 1. Kumar SK, Raikumar 5V. Dispenzieii A, et al. improved sun/ival in multiple myeloma and the impact at novel therapies. Blood. 2008:1112 251 5-2520. 2. Jema! A. Siege! R, Ward E, ei al. 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