Pharmaceutical Fraud and Abuse in the United States, 1996-2010

able diagnostic tools, and FUO-AMR is as high as 5%. Financial Disclosure: None reported. This result is important considering the potential pro- Funding/Support: This project was supported by an un- gressive expansion of preemptive therapy use in routine restricted grant from Merck Sharp & Dohme, Italy. practice. Other Members of the Hema e-Chart Group, Italy: C. Bacterial infections are the most frequent cause of in- Cattaneo, U. O. Ematologia, Spedali Civili, Brescia; R. Fanci, fectious complications in cases of AML. In our survey, Azienda Ospedaliera–Universitaria Careggi–Ematologia, the ratio of gram-positive to gram-negative bacteria ap- Firenze; A. Bonini A, Ematologia, Arciospedale S. Maria proached one. Strikingly, more than 25% of proven bac- Nuova, Reggio Emilia; N. Vianelli, Istituto Seragnoli– terial infections were polymicrobial and 9% were mixed Università di Bologna, Bologna; M. Riva, Ematologia e infections, of which most were fungal and bacterial. Centro Trapianti Midollo, Ospedale Niguarda Ca’ Granda, The incidence of IFDs observed confirmed a trend of Milano; L. Beltrame, U. O. Ematologia Policlinico Univer- increased frequency of mold infections relative to yeast sitario Tor Vergata, Roma; M. Musso, Emato-oncologia infections; the ratio in our study was 5:1.1 Considering ed Unità, Trapianti Midollo Osseo, La Maddalena, Palermo; the high number of observed FUO episodes, we cannot G. Rossi, Ematologia, IRCCS Casa Sollievo della Soffer- exclude that the incidence of IFDs might be higher. The enza, San Giovanni Rotondo; N. Filardi, Ematologia, AMR due to IFDs is decreasing, confirming recent data Azienda Ospedaliera–S. Carlo, Potenza; A. Piccin, Ema- that report a similar trend.6 tologia, Ospedale Generale, Bolzano; A. Cuneo, Emato- The incidence of FUO is still high and remains one logia, Azienda Ospedaliera–Universitaria Arcispedale of the most challenging issues faced by hematologists. S. Anna, Ferrara; M. G. Garzia, Ematologia Azienda Whether viral infections in AMLs are really rare or un- Ospedaliera S. Camillo Forlanini, Roma; S. Sannicolò, derestimated is yet to be verified. Ematologia, Umberto I, Mestre; M. Morselli, Ematologia, Hema e-Chart allows the prospective collection and Policlinico Universitario di Modena e Reggio; U. Salvatori, analysis of targeted high-quality data derived from clini- Ematologia Ospedale Civile “Ca Foncello,” Treviso; T. cal experience and provides information on the epide- Aloisi, Ematologia, Università di Perugia. miologic patterns of infectious complications in AMLs, 1. Pagano L, Caira M, Candoni A, et al. The epidemiology of fungal infections which are rarely studied in prospective multicenter ob- in patients with hematologic malignancies: the SEIFEM-2004 study. servational trials. Our registry appears to be very useful Haematologica. 2006;91(8):1068-1075. particularly in the early phases of AML, when infectious 2. Nørgaard M, Larsson H, Pedersen G, Schønheyder HC, Sørensen HT. Risk of bacteraemia and mortality in patients with haematological malignancies. Clin complications are more frequent and thus affect the sched- Microbiol Infect. 2006;12(3):217-223. ule of chemotherapy. 3. Faensen D, Claus H, Benzler J, et al. SurvNet@RKI—a multistate electronic re- porting system for communicable diseases. Euro Surveill. 2006;11(4):100-103. 4. Angelow A, Schmidt M, Weitmann K, et al; German Transregional Collab- Livo Pagano, MD orative Research Centre on Molecular Pathogenesis and Therapy of Inflam- Morena Caira, MD matory Dilated Cardiomyopathy. Methods and implementation of a central biosample and data management in a three-centre clinical study. Comput Meth- Annamaria Nosari, MD ods Programs Biomed. 2008;91(1):82-90. Giuseppe Rossi, MD 5. Pagano L, Caira M, Nosari A, et al; Hema E-Chart Group Italy. Hema e- Pierluigi Viale, MD Chart: Italian Registry for prospective analysis of epidemiology, management and outcome of febrile events in patients with hematological malignancies. Franco Aversa, MD J Chemother. 2010;22(1):20-24. Mario Tumbarello, MD 6. Pagano L, Caira M, Picardi M, et al. Invasive Aspergillosis in patients with acute leukemia: update on morbidity and mortality—SEIFEM-C Report. Clin for the Hema e-Chart Group, Italy Infect Dis. 2007;44(11):1524-1525. AuthorAffiliations: Ematologia, Università Cattolica S. Cuore, Rome, Italy (Drs Pagano and Caira); Ematologia e Centro Trapianti Midollo, Ospedale Niguarda Ca’ Granda, Milan, Italy (Dr Nosari); U. O. Ematologia, Pharmaceutical Fraud and Abuse Spedali Civili, Brescia, Italy (Dr Rossi); Clinica di Malat- in the United States, 1996-2010 tie Infettive, Università di Bologna, Bologna, Italy (Dr Viale); Ematologia, Università di Perugia, Perugia, Italy rescription drug spending totaled $234 billion in (Dr Aversa); and Malattie Infettive Università Cattolica 2008 (up from $40 billion in 1990) and ac- S. Cuore, Rome (Dr Tumbarello). P counted for 10% of health care expenditures.1 Correspondence: Dr Pagano, Istituto di Ematologia, Uni- Pharmaceutical fraud may be an important component versità Cattolica del Sacro Cuore, Largo Francesco Vito, of health care costs. Between 1996 and 2005, $3.6 bil- 1, I-00168 Rome, Italia ([email protected]). lion was recovered for 13 pharmaceutical fraud cases ini- Author Contributions: Study concept and design: Pa- tiated by “whistle blowers” (termed qui tam relators). gano, Nosari, Rossi, Viale, and Aversa. Acquisition of data: These recoveries, despite accounting for 3% of the num- Caira and Aversa. Analysis and interpretation of data: Pa- ber of federal fraud cases involving health care, ac- gano, Caira, Nosari, Rossi, Viale, Aversa, and Tum- counted for 40% of federal fraud financial recoveries in- barello. Drafting of the manuscript: Pagano and Caira. Criti- volving qui tam relators.2 We report on pharmaceutical cal revision of the manuscript for important intellectual fraud investigations completed between 1996 and 2010 content: Pagano, Nosari, Rossi, Viale, Aversa, and Tum- regardless of qui tam relator involvement status. barello. Statistical analysis: Tumbarello. Study supervi- sion: Pagano, Nosari, Rossi, Viale, Aversa, and Tum- Methods. All cases involved pharmaceutical manufac- barello. turers and False Claims Act (FCA) violations (the most

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 Table. Settled Federal False Claims Act Cases Involving Pharmaceutical Manufacturers (1996-2010)

$ (in Millions)

Amount Recovered by Total Qui Tam Name of Company Year Recovery Relators Reasons Occupation of Qui Tam Relator GlaxoSmithKline, Middlesex, 2010 750 96 Selling contaminated drugs Pharmaceutical quality manager England Allergan, Naperville, Illinois 2010 600 38 Off-label marketing A physician and 5 sales representatives AstraZeneca, London, England 2010 520 45 Off-label marketing Physicians involved in clinical trials and sales representative Novartis, Basel, Switzerland 2010 423 25 Off-label marketing Company employees Pfizer, New York, New York 2009 2300 102 Misbranding, illegal 6 Sales representative marketing, and kickbacks Eli Lilly and Co, Indianapolis, 2009 1400 79 Off-label marketing 5 Sales representatives Indiana Forest Laboratories, New York, 2009 313 14 Misbranding or off-label 3 Sales representatives New York marketing Purdue Pharma LP and Purdue 2007 634 None Misbranding None Frederick Co, Stamford, Connecticut Bristol-Myers Squibb, New 2007 515 50 Fraudulent marketing and 7 Employees including 1 York, New York pricing medical liaison Aventis, Strasbourg, France. 2007 180 33 Fraudulent pricing Ven-A-Care of Florida Keys Inc Jazz Pharmaceuticals, Palo Alto, 2007 20 NA Off-label use Former sales representative California Cell Therapeutics Inc, Seattle, 2007 11 NA Off-label use Sales representative Washington Schering-Plough, Kenilworth, 2006 435 31 Fraudulent marketing and Company managers New Jersey pricing InterMune Inc, Brisbane, 2006 37 None Off-label marketing None California Baxter International, Deerfield, 2006 9 2 Fraudulent pricing Pharmacist Illinois Serono, Geneva, Switzerland 2005 567 52 Fraudulent marketing 3 Sales representatives GlaxoSmithKline 2005 150 26 Fraudulent marketing and Pharmacists pricing King Pharmaceutical, Bristol, 2005 124 8 Fraudulent pricing Directory of accounts at Tennessee subsidiary Novartis/OPI Properties 2005 45 None Off-label marketing None Roxane, Columbus, Ohio 2005 10 2 Fraudulent pricing Pharmacist Parke-Davis 2004 430 27 Fraudulent marketing Medical liaison (Pfizer/Warner-Lambert) Schering-Plough 2004 345 31 Fraudulent pricing Subsidiary employees Warrick Pharmaceutical 2004 27 5 Fraudulent pricing Pharmacist (Schering Plough) Abbott Laboratories, Abbot 2003 600 None Fraudulent pricing None Park, Illinois AstraZeneca 2003 355 48 Fraudulent marketing and TAP Pharmaceuticals vice pricing president of sales and a urologist Bayer Corp, Pittsburgh, 2003 257 34 Fraudulent pricing Company executive Pennsylvania Dey Pharma (Merck), Basking 2003 19 2 Fraudulent pricing Pharmacist Ridge, New Jersey Pfizer 2002 49 6 Fraudulent pricing National account manager for subsidiary TAP Pharmaceuticals Products 2001 875 78 Fraudulent pricing TAP Pharmaceuticalsvice Inc, Deerfield, Illinois president of sales Bayer Corp 2001 14 2 Fraudulent pricing Pharmacist Novartis 1999 8 None Fraudulent pricing None

Abbreviation: NA, not available.

commonly used law invoked in health care fraud pros- civil penalties of $5500 to $11 000 per claim for submit- ecutions). The FCA allows private citizens (qui tam re- ting false claims to the government.3 Data were from Lexis/ lators) to file antifraud actions on behalf of the govern- Nexis News databases (search terms included Pharma- ment and imposes liability of up to triple damages and ceutical fraud, False Claims Act, and Qui tam) and

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 Department of Justice Web site (1996-2010). Cases with awards as high as $102 million being awarded to qui tam less than $5 million in financial recoveries were ex- relators and qui tam relators having initiated 77% of phar- cluded. Data were abstracted on allegations, financial maceutical cases, their central role in identifying fraudu- settlements, occupations of and payments to qui tam re- lent pharmaceutical marketing practices is likely to lators, and date of settlement. expand. Our analysis has limitations, primarily absence of a Results. Total FCA recoveries for pharmaceutical central data repository. Despite this, our analysis high- fraud were $8 million during 1996 through 2000 (1 lights the observation that many of the largest pharma- case), $3.9 billion during 2001 through 2005 (15 ceutical corporations have been implicated in health care cases), and $8.1 billion during 2006 through 2010 (15 fraud cases, sometimes more than once. With expan- cases) (Table). Almost all cases involved marketing sion of government health care, investigations of phar- violations. Off-label or fraudulent marketing and mis- maceutical manufacturers will continue to result in sub- branding charges were implicated in 15 cases ($8.7 stantial financial recoveries. Our findings raise concern billion), billing fraud in 17 cases ($3.9 billion), and that despite these recoveries, industrywide changes in the receiving kick-backs in 1 case ($2.3 billion). One case way pharmaceutical corporations conduct marketing ac- resolved allegations of producing defective pharma- tivities are needed. ceuticals ($750 million). Six settlements included criminal and civil fines. Zaina P. Qureshi, PhD, MPH With respect to individual cases, 1 company was in- Oliver Sartor, MD volved in 3 cases, and 3 companies were involved in 2 Sudha Xirasagar, MBBS, PhD cases each. The largest recovery, $2.3 billion (19% of re- Ying Liu, PhD coveries) in 2009, was for misbranding, illegal market- Charles L. Bennett, MD, PhD, MPP ing, and paying kickbacks to physicians for prescribing Author Affiliations: South Carolina Center of Eco- a cox-2 inhibitor that is no longer marketed. The sec- nomic Excellence for Medication Safety and Efficacy ond largest recovery, $1.4 billion (11% of recoveries), also and the Southern Network on Adverse Reactions in 2009, was for off-label marketing of a drug approved (SONAR), Department of Clinical Pharmacy and Out- to treat bipolar disorder and severe schizophrenia for off- come Sciences, South Carolina College of Pharmacy label administration to children in foster care, persons (Drs Qureshi and Bennett), and Department of Health with insomnia, and elderly patients in nursing homes. Policy and Management, Arnold School of Public In 2010, $750 million (6% of recoveries) was recovered Health (Drs Xirasagar and Bennett), University of when a pharmaceutical manufacturer was implicated for South Carolina, Columbia; Indiana University School selling contaminated drugs from a factory located in of Public and Environmental Affairs, Bloomington (Dr Puerto Rico. Liu); Tulane Cancer Center and Departments of Medi- Qui tam relators initiated 77% of the cases (median cine and Urology, Tulane Medical School, New qui tam award of $31 million and total qui tam awards of Orleans, Louisiana (Dr Sartor); and Hollings Cancer $836 million). The largest qui tam awards were $102 mil- Center, Medical University of South Carolina, Charles- lion (12% of qui tam recoveries), $96 million (11%), $79 ton (Dr Bennett). million (9%), and $78 million (9%). All involved cases Correspondence: Dr Bennett, South Carolina College of of marketing fraud and resulted in recoveries from be- Pharmacy, 715 Sumter St, Ste 311, Columbia, SC 29208 tween $750 million to $2.3 billion. ([email protected]). Author Contributions: Study concept and design: Qureshi, Comment. Since 1996, $12 billion has been recovered Sartor, and Bennett. Acquisition of data: Qureshi and in concluding 31 pharmaceutical FCA prosecutions. Mean Bennett. Analysis and interpretation of data: Qureshi, per case recovery has doubled since 2006 to $550 mil- Sartor, Xirasagar, Liu, and Bennett. Drafting of the lion from the prior 5 years, although the same number manuscript: Qureshi, Sartor, Xirasagar, Liu, and Ben- of cases, 3 per year, was concluded. In interpreting our nett. Critical revision of the manuscript for important in- findings several factors should be considered. tellectual content: Qureshi, Sartor, Xirasagar, Liu, and Settlements and fines resolving allegations of fraudu- Bennett. Statistical analysis: Qureshi, Xirasagar, and lent marketing practices accounted for the largest recov- Bennett. Obtained funding: Bennett. Administrative, tech- eries. Mello et al4 highlighted the central role of litiga- nical, and material support: Liu and Bennett. Study su- tion, and subsequent large monetary fines and pervision: Sartor and Bennett. settlements and institution of corporate integrity Financial Disclosure: None reported. agreements (that require institution of practices Funding/Support: This study was supported in part by designed to prevent recidivism), in protecting against the National Cancer Institute (1R01CA 102713-01) (Dr fraudulent marketing practices. Recently, the Depart- Bennett) and the South Carolina Center of Economic ment of Health and Human Services raised the stakes Excellence Center for Medication Safety initiative (Dr even higher in barring the chief executive officer of Bennett). one firm from negotiating future contracts with federal 5 health care providers. 1. Almashat S, Preston C, Waterman T, Wolfe S. Rapidly increasing criminal and Qui tam relators, usually employees or former em- civil monetary penalties against the pharmaceutical industry: 1991 to 2010. http: //www.citizen.org/documents/rapidlyincreasingcriminalandcivilpenalties.pdf. Ac- ployees of pharmaceutical corporations, are the pri- cessed April 28, 2011. mary information source for fraud investigations.2 With 2. Kesselheim AS, Studdert DM. Whistleblower-initiated enforcement actions

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 against health care fraud and abuse in the United States, 1996 to 2005. Ann Unlike other trials using CBT in cardiac populations Intern Med. 2008;149(5):342-349. 3. False Claims Act. 31 USC §3729-3733. that have failed to produce significant survival ben- 4. Mello MM, Studdert DM, Brennan TA. Shifting terrain in the regulation of efits,5 this study demonstrates the positive effects of a CBT off-label promotion of pharmaceuticals. NEnglJMed. 2009;360(15):1557- approach in the secondary prevention of CAD. How- 1566. 5. Spitzer K. The administration targets a drug CEO in a troubling precedent. 2011. ever, we hypothesize that while the contribution of pu- http://online.wsj.com/article. Accessed April 28, 2011. tative influences such as depression, anxiety, and social support remains unaccounted for in this study, it is likely that they are, in fact, elucidating the observed relation- ship between survival and treatment. COMMENTS AND OPINIONS Adrienne E. O’Neil, BA(Hons) Kristy Sanderson, BSc(Hons), PhD Author Affiliations: Department of Epidemiology and Pre- The Use of Cognitive Behavioral Therapy ventive Medicine, Monash University, Alfred Hospital, for Secondary Prevention in Patients With Prahran, Victoria, Australia (Ms O’Neil); and Menzies Re- Coronary Heart Disease search Institute Tasmania, University of Tasmania, Ho- bart, Australia (Dr Sanderson). ulliksson et al1 report the results of a random- Correspondence: Ms O’Neil, Department of Epidemiol- ized controlled trial of cognitive behavioral ogy and Preventive Medicine, Monash University, 89 G therapy (CBT), measuring its effects on Car- Commercial Rd, Alfred Hospital, Prahran, Victoria 3004, diovascular Disease (CVD) recurrence in 362 patients with Australia (adrienne.o’[email protected]). coronary artery disease. The authors found that, after 94 Financial Disclosure: None reported. months, the CBT group had a 41% lower rate of fatal and 1. Gulliksson M, Burell G, Vessby B, Lundin L, Toss H, Sva¨rdsudd K. Random- nonfatal recurrent CVD events and 45% fewer recurrent ized controlled trial of cognitive behavioral therapy vs standard treatment to acute myocardial infarctions (AMIs) after adjustment for prevent recurrent cardiovascular events in patients with coronary heart dis- covariates. ease: Secondary Prevention in Uppsala Primary Health Care project (SUPRIM). Arch Intern Med. 2011;171(2):134-140. As the authors acknowledge, a large body of evidence 2. Schrader G, Cheok F, Hordacre AL, Guiver N. Predictors of depression three exists to link psychosocial factors such as depression, anxi- months after cardiac hospitalization. Psychosom Med. 2004;66(4):514-520. ety, and low social support to adverse cardiovascular out- 3. Frasure-Smith N, Lespe´rance F, Talajic M. Depression and 18-month prog- nosis after myocardial infarction. Circulation. 1995;91(4):999-1005. comes. There is compelling evidence that up to 42% of coro- 4. Frasure-Smith N, Lespe´rance F, Gravel G, et al. Social support, depression, nary patients experience depression.2 Comorbid depression, and mortality during the first year after myocardial infarction. Circulation. 2000; 3 101(16):1919-1924. even mild symptoms, can predict mortality, morbidity, and 5. Berkman LF, Blumenthal J, Burg M, et al; Enhancing Recovery in Coronary poorer clinical and well-being outcomes. Heart Disease Patients Investigators (ENRICHD). Effects of treating depres- Indeed, the intervention detailed by Gulliksson and sion and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients colleagues, which comprised a group-based CBT pro- (ENRICHD) Randomized Trial. JAMA. 2003;289(23):3106-3116. gram, addressed these psychosocial influences. Twenty- two–hour sessions were conducted over 1 year (plus usual medical care), with the overall goal of treatment to develop emotional and behavioral coping strategies for deal- In reply ing with stress. The focus was particularly on stress reactivity and We welcome the letter by O’Neil and Sanderson, which in stress behaviors characterized by negative affect like hostility, anxi- essence deals with the possibility that the results of our study1 ety, and depressive mood reactions [see eAppendix1] depend on group differences in depression, anxiety, and social However, in the absence of depression, anxiety, and support.Inapreviouspublication,thelevelsofdepressivemood, social support outcome measures documented in this anxiety, and social support among 346 cases from our present study, ascertaining the components of this group-based study population in their first post– myocardial infarction (MI) CBT intervention that led to these improvements is par- year were compared with the corresponding data among 610 ticularly difficult. Post-AMI depression has been identi- age-, sex-, and residency-matched referents from the general fied as a predictor of 1-year cardiac mortality, and more- population.2 Unexpectedly, we found no significant differences over, high levels of social support have been found to betweencasesandreferentsregardingeverydaylifestress,stress- provide a protective influence from depression on mor- ful life events, vital exhaustion, depressive mood, coping, or op- tality.4 Because the authors have not discussed the me- timism. The cases reported a better social support—quality as diating role of these variables, readers can only specu- well as size of supporting network. late about their influence. Because all these factors are well-known risk factors for Furthermore, while this study highlights the benefits fatal and nonfatal MI, we concluded that things must have of a protocol-driven program, whether its effectiveness changed during the first post-MI year, perhaps with more is fully explained by the CBT approach to treatment, from support from family and other social network components. enhanced social support via regular, face-to-face, group- However, there were large differences by sex, with female based contact with peers or via improvements in anxi- cases having the worst situation. ety and depression as a direct consequence of therapy or In our present study we found no significant differences as a byproduct of other behavioral modifications, re- between the intervention and the reference group regard- mains unanswered. ing everyday life stress, stressful life events, vital exhaus-

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