Bioethical InquiryDOI 10.1007/s11673-010-9208-8From Evidence-based Medicine to Marketing-basedMedicine: Evidence from Internal Industry DocumentsGlen I. Spielmans & Peter I. ParryReceived: 2 October 2009 / Accepted: 15 December 2009# Springer Science+Business Media B.V. 2010Abstract While much excitement has been generated The larger issue is how do we face the outsidesurrounding evidence-based medicine, internal docu- world when they begin to criticize us forments from the pharmaceutical industry suggest that the suppressing data...publicly available evidence base may not accurately AstraZeneca publications manager in internalrepresent the underlying data regarding its products. The email 6 Dec 1999.industry and its associated medical communicationfirms state that publications in the medical literature According to conventional wisdom, we are firmlyprimarily serve marketing interests. Suppression grounded in evidence-based medicine (EBM). Whileand spinning of negative data and ghostwriting many forms of data, such as clinical experience, casehave emerged as tools to help manage medical studies, and uncontrolled trials can provide usefuljournal publications to best suit product sales, while information regarding patient care, the randomizeddisease mongering and market segmentation of controlled trial (RCT) reigns supreme. As RCTs allowphysicians are also used to efficiently maximize the direct comparison of drug and placebo or ofprofits. We propose that while evidence-based various compounds to one another, their rigor exceedsmedicine is a noble ideal, marketing-based medicine is that of other forms of research (Sackett et al. 1996).the current reality. As more and more RCTs are published in medical journals, we gain a better understanding of whatKeywords Evidence-based medicine . Marketing . works best. Interventions that fail to demonstrateMarketing-based medicine . Pharmaceutical industry . adequate efficacy and safety lose first line status andOlanzapine . Quetiapine are discarded over time. Patients, of course, benefit immensely from this meticulous scientific evaluation process, as they can rest assured that they are receiving treatments that show the greatest benefit and least risk. So the story goes. However, one couldG. I. Spielmans (*) argue that rather than EBM, we are actually nowDepartment of Psychology, Metropolitan State University,1450 Energy Park Drive, entrenched in marketing-based medicine (MBM), inSt. Paul, MN 55108, USA which science has largely been taken captive in thee-mail: firstname.lastname@example.org name of increasing profits for pharmaceutical firms. The case for MBM is based on several factors, eachP. I. ParryDepartment of Psychiatry, Flinders University, of which influences the knowledge and practice ofAdelaide, Australia medicine, including: suppression and spinning of
Bioethical Inquirynegative data, ghostwriting, disease mongering, market this point. It mentioned that a good publication plansegmentation of physicians, and failure of regulatory “targets such information toward highly reputable, peer-authorities and peer-reviewed journals (despite reviewed journals (which are today viewed as theincreasing efforts) to police what, in the words of single most trusted source of information by USMarcia Angell, former chief-editor of the New physicians, over that of continuing medical educa-England Journal of Medicine, is a “broken system” tion, thus enhancing its scientific imprimatur, while(Angell 2008, 1069). building relationships with the journals and their Richard Smith, former chief-editor of the British readership)” (Scarpuzza undated). Similarly, oneMedical Journal, in a paper titled “Medical journals are memo from Pfizer asked “What is the purpose ofan extension of the marketing arm of pharmaceutical publication?” and responded with “High quality andcompanies” described the many and sophisticated ways timely publications optimize our ability to sell Zoloftin which drug trial data can be manipulated. He said it [the antidepressant sertraline] most effectively”took “almost a quarter of a century editing for the BMJ (Clary 2000). The same document makes it clear thatto wake up to what was happening” (Smith 2005, the data from sponsored drug trials belongs to thee138). Such manipulation was indeed difficult to company and the “purpose of data is to support, directlydiscern in the past, but the release of internal or indirectly, marketing of our product” (see Fig. 1).pharmaceutical industry documents has shed light on PeerView is a company that provides varioushow marketing has come to trump science (e.g., services to the pharmaceutical industry, including “...Applbaum 2008; Steinman et al. 2004). products that support publication strategy and other These documents have been released by courts where commercialization processes for our pharmaceuticalpharmaceutical companies have been subject to litiga- and biotech clients”. The CEO of PeerView statedtion from class action plaintiffs and government that “...most pharma and biotech companies recognizeprosecutors. They allow for close examination of many the significant impact that the clear and consistentpractices that are not typically widely publicized. publication of results will have on subsequentIndeed, although many internal industry documents are commercialization efforts” (Villarroel 2007, 2). Anlegally available on the internet, there are as yet few Eli Lilly internal document refers to new strategicpublications in the biomedical literature based primarily planning for the branding of its antipsychotic drugon internal industry sources. These internal documents, olanzapine (Zyprexa). The document states underas well as material drawn from other sources, provide “strategic imperatives,” that a goal is to “developinsight into the intersection between marketing and scientific research and publication plan that enhancesscience within the pharmaceutical industry. While the credibility of the new brand positioning and enablesdocuments examined in this paper reflect our the achievement of the ideal positioning” (Eli Lillyspecialties in mental health, the manipulation of 2001a). To help meet this goal, it is mentioned thatdrug trial data they expose are clearly not limited to the company should “mine existing data to generateonly this field, as evidenced by situations involving and publish findings that support the reasons tomedications for osteoporosis (Washburn 2005) or believe the brand promise” (Eli Lilly 2001a).non-steroidal anti-inflammatory agents (Ross et al.2008; Smith 2006).Science as MarketingEspecially given the current focus on using evidence-based treatments, it comes as no surprise that thepharmaceutical industry values scientific data thatdemonstrate efficacy and/or safety of their products.These data are particularly valuable when translated intoarticles in high impact peer-reviewed journals. A Fig. 1 Excerpt from document regarding marketing of sertralinepharmaceutical industry trade publication emphasized (Pfizer)
Bioethical Inquiry Science is clearly related to marketing goals, which litigation suggest a quite different story. The results ofof course is not necessarily problematic. If a product research comparing the two compounds are found inis supported by good data, then few would find it an AstraZeneca document, in which it was concludedunethical to disseminate such information. But what if that quetiapine possessed weaker efficacy than halo-the science is not supportive; what if a drug does not peridol (AstraZeneca 2000; see Fig. 2). The companydemonstrate efficacy or is dangerous? What if a document was produced in March 2000, two monthsstudy’s results do not jive with the brand promise? prior to the rosy presentation of quetiapine’s efficacy. An email regarding this data, from a publications manager at AstraZeneca, stated in part: “The data don’tSuppressing and Spinning Negative Data look good. In fact, I don’t know how we can get a paper out of this” (Tumas 2000; see Fig. 3). The leadWhile drugs still enjoy patent protection, pharmaceu- researcher on the 2000 paper, when queriedtical companies typically provide the lion’s share of recently by a journalist regarding the claim thatthe funding to investigate their products. Journal quetiapine is “significantly superior” to haloperidol,articles that tout the positive features of a drug help conceded that the claim was indeed an exaggerationto keep product moving from pharmacy shelves. The yet maintained that the data analysis was accuratedata which form the backbone of these articles is (Olson 2009).controlled by the sponsor. It is well-known that AstraZeneca also commissioned a comparativestudies funded by a drug manufacturer are much trial known as Study 15. In this trial, patients inmore likely to yield positive results than studies of the partial to full remission of schizophrenia weresame drug conducted by researchers not tied to the randomly assigned to receive either haloperidol orsponsor (Lexchin et al. 2003). One main reason for quetiapine. At the end of the one-year trial, patientsthis finding is that drug manufacturers are under no receiving haloperidol fared better in terms of symp-obligation to publish negative results. Indeed, if the tom ratings and had significantly fewer psychoticprimary goal of publicly traded drug firms is to relapses relative to patients on quetiapine. Thesemaximize return to shareholders, it makes no sense at negative results were not published. Rather, as statedall to publish results that cast a drug in a negative in an internal email, “cherry picking” occurredlight. (Tumas 1999; see Fig. 4). On some measures of cognitive functioning, quetiapine significantly out-Quetiapine: Internal vs. Published Data performed haloperidol, which was the basis for a publication (Velligan et al. 2002). The abstractAstraZeneca’s antipsychotic drug quetiapine (Seroquel) included the statement: “Treatment with quetiapineis one of a class of drugs known as atypical anti- at higher doses relative to haloperidol appears to havepsychotics or second-generation antipsychotics. In a positive impact on important domains of cognitive2000, data comparing quetiapine to haloperidol, an performance that have been found to predict roleolder, generic antipsychotic, were presented at the function and community outcomes in patients withannual convention of the American Psychiatric Associ- schizophrenia” (239). While the paper suggested theation. In a press release, the author of the presentation likelihood of better community outcomes, it failed tostated: “I hope that our findings help physicians better mention the increased risk of psychotic relapse andunderstand the dramatic benefits of newer medications the relatively poorer scores on symptom measureslike Seroquel, because, if they do, we may be able to compared to haloperidol. In an internal email twohelp ensure patients receive these medications first” other “buried trials” are mentioned, in addition to a(Olson 2009). The presentation, in line with the press third trial that was pending potential suppression atrelease, shows that quetiapine possessed a statistically the time of the message (Tumas 1999).significant advantage over haloperidol in inducingtreatment response among patients with schizophrenia. Antidepressants: Internal vs. Published DataThese data were based on a meta-analysis of fourstudies that compared quetiapine and haloperidol. Such tactics are not unique to any individualHowever, documents released by the company during company; they are quite plainly widespread. Indeed,
Bioethical InquiryFig. 2 AstraZeneca internalmeta-analysis of quetiapinevs. competitors/placeboone investigator calls data suppression “the dirty little were positive. Only one-third of studies findingsecret” of medical research (Dawdy 2008). The negative results were published, and over half ofresearcher, Erick Turner, led a team which compared those were published claiming that the study actuallypublished trials of antidepressants versus their unpub- found positive outcomes.lished counterparts. Pharmaceutical firms must submit How can a trial go from showing questionable ortheir clinical trial data to the Food and Drug no efficacy to a definitive statement of efficacy?Administration (FDA) as part of their application for Various publications did the following: failing toapproval for marketing the drugs in the United States. report data from all participants (those who droppedTurner’s team examined the publication status of trials out due to lack of efficacy or adverse events weresubmitted to the FDA for all antidepressants approved excluded), reporting data from only one site of aby the agency from 1987 through 2004 (Turner et al. multisite trial, reporting data for something called2008a).They found that 97% of the trials in which the an “efficacy subset,” which is an apparent euphe-FDA review found a positive outcome were then mism for scrubbing inconvenient data from thepublished in a journal. Some trials yielded a “ques- dataset, and by switching primary outcomes posttionable” outcome, in which the data on the primary hoc (Turner et al. 2008b). For each of the 12outcome was negative but some secondary measures antidepressants, at least one trial was unpublished orfound the drug was efficacious. Half of the trials in at least one trial was published with conclusionswhich the FDA review found a “questionable” conflicting with FDA review of the data. Thus, oneoutcome were published and half were not. Of the cannot blame one or two “bad apples,” as it appears“questionable outcome” trials that were published in a data suppression is part of the industry’s standardmedical journal, all were written up as if the results operating procedure.Fig. 3 AstraZeneca emailregarding meta-analysis ofSeroquel vs. competitors/placebo
Bioethical InquiryFig. 4 AstraZeneca emailregarding “cherry picking”and “suppressing data” Along the same line, data were selectively published placebo participants experiencing “emotional labil-regarding antidepressant use among children and ity,” (a term used to describe “suicidal ideation/adolescents (Whittington et al. 2004). One notable gestures”). An internal company report of sideexample is a study (known as Study 329) comparing effects of paroxetine yields more—eight partici-paroxetine (a serotonin-reuptake inhibitor antidepres- pants experienced suicidal gestures or deliberatesant, manufactured by Smith Kline Beecham (SKB) self-harm and seven cases of hostility on paroxetinewhich is now GlaxoSmithKline (GSK) under the brand compared to zero on placebo. An earlier draft ofname Paxil), imipramine (an older, tricyclic antidepres- the results stated that “worsening depression,sant), and placebo in the treatment of adolescent emotional lability, and hostility were considereddepression. Study 329, sponsored by SKB/GSK, related or possibly related to treatment,” yet thewas published in 2001 with a clear message stated published version claims that only one case ofin the abstract: “paroxetine is generally well headache was considered related to paroxetine.tolerated and effective for major depression in Thus, a drug failed to demonstrate efficacy on allchildren” (Keller et al. 2001, 762). However, the eight pre-specified primary and secondary efficacytrial data indicated that the drug was neither measures, is related to more treatment-emergentefficacious nor particularly safe. suicidal gestures and hostility, and yet is claimed in How did this come about? During litigation, GSK a peer-reviewed journal to be safe and effectivereleased documents concerning the study, which were (Jureidini et al. 2008).then compared with the published version. The study Internal discussion about whether the companyprotocol and its revisions named two primary out- should even publish the study included an email thatcome measures but both failed to demonstrate a read: “originally we had planned to do extensivesignificant advantage over placebo at study endpoint. media relations surrounding this study until weThe original study protocol also had six secondary actually viewed the results. Essentially the study didmeasures, all of which likewise failed to show not really show Paxil was effective in treatingefficacy. In the published version of the study, four adolescent depression, which is not something weof eight measures were reported as positive (rather want to publicize” (White 2001). Nonetheless, thethan zero of eight)—all were on measures not called study was published and, in an internal documentfor in the study protocol or revisions, a classic case of distributed to all company representatives sellingdata fishing. paroxetine, was labelled a “cutting-edge landmark The study publication referred to six of 93 study” demonstrating “REMARKABLE” efficacy andparoxetine participants compared to one of 87 safety for the drug (Hawkins 2001).
Bioethical InquiryGhostwriting independence to the paper (Moffat and Elliott 2007). While the audience may look suspiciously on a paperPublications provide important information regarding with an all-corporate authorship line, the presence ofdrug safety and efficacy. These articles are probably an academic author lends the air of independence andmost influential when they are perceived as independent prestige, making the article appear more credible. Thefrom the drug company. A physician may view an academic authors may review an outline or draft, butarticle with a corporate authorship line as biased yet typically perform little writing. For example, anview the same article as more credible if independent internal Eli Lilly document discusses “drafting a fullacademic authors were listed as contributors. However, feature for review” by an influential author or perhapsacademics are often busy with research obligations, having the author develop the article after reviewingspeaking engagements, teaching, administrative the outline provided by the company or its associatedduties, clinical work and other tasks and some are writing firm (Eli Lilly undated-a).not particularly skilled at writing. Ghostwritingovercomes these limitations. A pharmaceutical firm Ghostwriting in the Antidepressant Literaturemay design a paper in-house or contract with amedical education and communication company The prevalence of ghostwriting is obviously hard to(MECC) to write a manuscript. determine. A few studies have suggested that approximately 10% of papers are ghostwritten, butWriting Firms these are based upon self-report surveys, which likely under-report the incidence of such behaviourOne example is Sunvalley Communication (http:// (Flanagin et al. 1998; Mowatt et al. 2002).sunvalleycommunication.com). Their website describes Through litigation, one research team gainedseveral important services (Hofland undated). They access to documents regarding the antidepressantproduce papers closely linked with “brand strategies” sertraline (Zoloft)—remember that according to itsand also create a publication strategy to “align with manufacturer, publications were primarily meant tomarketing strategy” and “tweak” their message to maximize sales of this drug. A MECC named Currentbest suit the publication and target audience. This firm Medical Directions (CMD) contracted with Pfizer toalso offers to compose papers for researchers and produce 85 publications regarding the drug. Accord-graduate students based on an outline provided by the ing to one analysis, between 18% and 40% of articlesresearcher—and its involvement can be “strictly confi- on sertraline from 1998−2000 were managed bydential” (Sunvalley Communication undated). Another CMD (Sismondo 2007). The majority of the CMDcompany, Dianthus Medical, receives “key messages” articles featured academic authors—one authorfrom pharmaceutical clients and writes a manuscript appeared in 12 such publications. In addition, theoutline, which they recommend receives approval from articles managed by CMD appeared in significantlyall authors who will be listed on the paper. They then higher-impact journals compared to non-CMDwrite the first draft of the paper, “ensuring that your articles on sertraline. One document from CMDmessage is communicated in the most effective way,” lists a number of sertraline publications in variousthen pass it along for the client’s approval. Revisions stages of completion—several contain notes such asare made and the paper prepared for submission to “Author TBD”—indicating that while a medicalthe journal (Dianthus Medical undated). This com- writing firm was completing (or had completed) thepany lists such pharmaceutical giants as AstraZeneca, paper, a so-called “author” had yet to lend his orGlaxoSmithKline, Lilly, and Wyeth among its clients. her name to the piece. Other notes include suchSunvalley and Dianthus are but two of many such comments as “outline sent to Pfizer for approval”companies; descriptions of similar firms have been (Current Medical Directions 1999).provided elsewhere (Sismondo 2007). Researchers who investigated the CMD-affiliated The process is relatively simple: A ghostwriter articles made the crucial point that traditional scienceincludes messages to maximize the marketing power relies on authors having access to the underlying rawof the publication while one or more “honorary” data that forms the basis of publications (Healy andacademic authors lend their names, titles, and purported Cattell 2003). However, publications written by drug
Bioethical Inquiryfirms or MECCs are often based on proprietary data placebo washout, followed by 8 weeks of patientsbelonging to the drug firm. If an academic author receiving either drug or placebo. It should becannot vouch for the underlying data and did not obvious that the comparison of efficacy and safetywrite the paper, then how can he or she be anything between drug and placebo should begin during theother than window dressing for a marketing device fourth week, when half of the participants havewrapped in scientific packaging? Healy and Cattell started receiving active medication. Yet some(2003) note that a case of completed suicide and manufacturers of antidepressants counted suicidalseveral cases of suicidal ideation were not reported in behaviour in the placebo wash-out phase againstthe CMD-authored pieces. The first draft of the paper placebo in their comparisons of drug to placebo.from Study 329, which clearly overstated benefits and Comparing suicidal acts on 11 weeks on placebo tounderstated risks, was also written by a MECC 8 weeks on a drug helped to drive up apparent rates(McHenry and Jureidini 2008). The lead author of of suicidal behaviour on placebo, which made thethe study said that he only reviewed data tables, not drugs appear safe in comparison. Indeed, an articlethe raw data (BBC 2007). Thus, honorary academic was published in 1995 allegedly showing thatauthors are not just padding their vitae, they are also paroxetine reduces suicidality. The academic authorpotentially harming public health when they fail to admitted that he had not seen the actual raw data;carefully review data presented in studies on which rather, he had been provided data tables by thetheir names appear as authors. manufacturer, which he then helped to convert into While honorary authors are typically affiliated with an article (Glenmullen 2007). However, the datauniversities, non-academic clinicians are also some- in the article included suicide attempts whichtimes utilized to author papers in an unconventional occurred during the placebo washout phase,manner. GlaxoSmithKline used such a program to though this was not stated in the manuscript.promote its antidepressant paroxetine (Paxil). The plan, GSK has since posted its own analysis online, inwhich used the interesting acronym “CASPPER—Case which it notes an increased risk of suicidalStudy Publications for Peer Review” had the following behaviour among patients taking paroxetine rela-main goal: “Publications of such articles will benefit the tive to placebo (GlaxoSmithKline undated). Nearlysales force by expanding the database of published data anyone reading a journal article will assume that theto support Paxil” (SmithKlineBeecham undated). If a named authors had access to raw data rather thanphysician mentioned a success with paroxetine, sales misleading data tables provided by a drug firm.representatives were to encourage the physician to While not technically ghost authorship, the mannerwrite a case study. Sales reps were instructed to in which the data were translated into final form isacknowledge the importance of the physician’s time clearly outside of the norms of science.and offer to save precious time through the contractededitorial staff, who could assist with everything from Investigator-initiated Trials and Opinion Leadersliterature searches to editing the paper. It seems thatphysicians had relatively little leeway regarding their Further evidence on the extent that companies,papers—one excerpt from a company document stated rather than honorary authors, own and manage drugthat the editorial team would “work closely with trial data comes from an internal AstraZeneca emailcontributing physicians to ensure rapid dissemination from the “Global Brand Manager—Seroquel” (que-of consistent data and messages”. It is likely that data tiapine) to the “SEROQUEL GLOBAL BRANDinconsistent with the company’s marketing was not part TEAM” dated “8/7/2003” on the subject “IITof the publication plan. At least five journals reportedly benchmarking report” (Hagger 2003). IIT standspublished papers produced through CASPERR for “Investigator-initiated trials” where an academic(Edwards 2009a). or clinician from outside the company is sourced as Placebo-controlled trials often include a placebo author of the trial. This email refers to a “series ofwash-out phase, in which all participants initially interviews carried out with internal AZ staff whoreceive placebo prior to some participants then were known to have worked for competitor compa-switching to the drug under investigation. For nies before as well as a number of KOL [key opinionexample, a study may use a 3-week period of leader] investigators from the UK, Italy, Germany
Bioethical Inquiryand Spain.” The email lists “key messages emerging typically in the academic setting and treat a minimalfrom the report: number of patients, if any...and serve on academic advisory boards, providing feedback to the Zyprexa& ...Lilly run a large and highly effective IIT Product and Brand Team” (Eli Lilly undated-b). Next program...They offer significant financial support in rank are “Consultant Thought Leaders...who are a but want control of the data in return. They are critical component of successful DTP (direct to able to spin the same data in many different ways physician i.e. sales rep) interventions and stimulate through an effective publications team. Negative the physicians at both the regional and the local level”. data usually remains well hidden. A September 2000 letter from a psychiatrist who was& Janssen have a well organized IIT plan...no IIT “one of our (Eli Lilly) speakers” on off-label use of data is allowed to be published without going olanzapine by primary care physicians suggested the through Janssen for approval, and communication local thought leader understood his role very well: is controlled by Janssen. High expectations are set on investigators who publish favourable results ...Once the ground is extensively plowed with but they are well rewarded for their involvement. good credible clinical information, not limited They seem less concerned than Lilly about by the GPP [Good Promotional Practice] guide- negative data reaching the public domain. lines that restrict information to schizophrenia& BMS IIT program is growing very fast in launched and acute mania, then (perhaps) turning the markets...most proposals are modified by BMS. sales force loose may be appropriate. I believe one of my strengths is in taking scientific Strategic focus is unlicensed indications... information and placing it in a clear, clinically useful format...Lilly could use someone with a Recommendations...for AstraZeneca...publica- strong clinical background but with strong tions should be more creative spinning the data, marketing instincts to assist them on this one aka Lilly...” (Eli Lilly 2000a). In fact an Eli Lilly document on “influencing keyplayers” in a passage headed “Investigator-InitiatedTrials, Relationship Building, and External Authorship”,states: Safety: Science or Marketing? Given our current business needs, it is important Weight gain, hyperglycaemia and precipitation of that funds spent on IITs predominantly support diabetes have been major concerns in the side effect the brand strategy. The review process should profiles of atypical antipsychotic medications. Internal consider whether they are on strategy, as well as company documents from Eli Lilly and AstraZeneca looking at whether they fill current gaps in our have a significant focus on the marketing manage- scientific data (Eli Lilly undated-b). ment of these side effects. KOLs with the right message can be very valuableto a company. An August 2002 email reporting on a Olanzapine: Managing Perceptions of Side EffectsJanssen-sponsored dinner presentation on metabolicside-effects of atypical antipsychotics in which a The transcript of a speech by the olanzapinespeaker “consistently implicated (Zyprexa) as a likely (Zyprexa) Brand Manager stated: “For Zyprexa,cause of type 2 diabetes or cardiac problems via weight gain is the ultimate topic to handle with skill.weight gain” noted “I think if I were with J [Janssen], Take this opportunity to tell the truth, to fight fire withI’d be throwing some cash at this chap to get his facts and to put this manageable side effect inmessage more widely known” (Eli Lilly 2002a). The perspective. Keep it simple, so that you don’tEli Lilly “Key Player Playbook” ranks contracted overwhelm the doctor with data” (Bandick 2001).academic experts as “Guild and Executive level Industry documents, read as a whole, give a strongThought leaders” who “are well respected and impression that ensuring adverse events “not over-acknowledged by their peers...influence the thinking whelm the doctor” means telling the doctor the bareand treatment practices of their peers...and are minimum about them.
Bioethical Inquiry Eli Lilly had been aware that “forty percent [onolanzapine] gained ≥7% body weight” (the FDA’s levelof “significant concern” for weight gain) from at least anearly trial—the HGAJ study—reported in minutes of ameeting with the US schizophrenia advisory panel inDecember 1995 (Eli Lilly 1995). The company receiveda letter of reprimand from the FDA in November 1996reminding that “the information on weight gain wasindeed included in the approved labelling, but as anadverse event, not a therapeutic benefit” (Feather 1996).An internal email among senior science executives inEli Lilly dated 24 November 1999, “subject:Olanzapine-associated Weight Changes (OWC)” notedthat, “...OWC has been and continues to be a top Fig. 6 Olanzapine diabetes sell sheet excerptpriority for the Zyprexa Product Team”. The email wenton to state: “Olanzapine is viewed to have more go about this? By neutralizing we mean level-associated weight gain than risperidone, seroquel, and ling the playing field, setting the record straighttraditional neuroleptics (Fact: the order of weight gain with the “comparable rates” message (Eli Lillyamong antipsychotics is: Clozapine>olanzapine> 2001b).seroquel>risperidone>traditional neuroleptics)”. Theemail noted “Physicians want more data” but also, Documents reveal Eli Lilly wanted to keep weight“Blanket detailing will be damaging since many gain and diabetes as separate issues that were notphysicians do not see OWC as an issue” (Breier 1999). linked. An undated review of “Olanzapine core safety Despite this early recognition that olanzapine caused and efficacy beliefs” stated: “A causal link betweenmore weight gain than other antipsychotics apart from Olanzapine therapy and diabetes has not beenclozapine, the marketing message for sales visits and established” (Eli Lilly undated-d). However, the sameCME became the “comparable rates” or “class side document also noted: “A potential reason for this iseffect” message—olanzapine was no different than that most of our studies were not designed (especiallyother atypical antipsychotic agents in inducing weight given the relatively short duration of these studies) togain or diabetes (Eli Lilly undated-c; Eli Lilly 2000b; study a link between Olanzapine therapy and Diabetes”.see Figs. 5 and 6). A September 2001 hyperglycaemia/ Documents reveal the company was in receipt of lettersdiabetes resource guide for sales reps states: from psychiatrists describing anecdotal reports of high rates of hyperglycaemia and diabetes from olanzapine, What do we mean by “neutralizing” physicians’ such as a letter dated 17 November 1999 stating: “we concerns about hyperglycemia and how do we have had eight patients out of possibly 35 on Zyprexa show up with high blood sugars...we certainly have never seen this with Haldol, Navane, Risperdal, and others to this extend [sic]” (Ventura County Behavioral Health Department 1999). An early report of data on adverse events from placebo-controlled trials of olan- zapine stated in larger font than the rest of the document: As of September 30, 1999, olanzapine-treated patients (N=4,234) who had no history of diabetes mellitus and whose baseline random plasma glucose levels were 140 mg/dL or lower were identified. Random glucose levels ≥160 mg/Fig. 5 Eli Lilly instructions to sales reps regarding weight gain dL but <200 mg/dL (possibly hyperglycemia, notissue necessarily diabetes) were observed in 2% of
Bioethical Inquiry patients. Of these patients, the random elevated “gaining the ear of senior leadership and articulating this glucose levels were found to be transient in 44% finding” (Brodie 2000). while they continued to receive olanzapine. Nonetheless the company still held to the marketing Random glucose levels ≥ 200 mg/dL (suggestive strategy of “comparable rates” and a December 2000 of possible diabetes) were observed in 1% of “diabetes situation analysis” on “Market Research on patients. Of these patients, the random elevated ‘message’” reported the “comparable rates” message glucose levels were found to be transient in 26% of “appears to be generally believable, makes ‘em think but them while they continued to receive olanzapine not all MDs change their basic premise” (Eli Lilly (Eli Lilly undated-e). 2000b). The message to the sales reps was still the In other words, despite the short-term nature of same in a September 2001 hyperglycaemia/diabetesmost of these trials, 3% of patients were exhibiting resource guide:possible new onset hyperglycaemia or diabetes and a Market research has shown that ALL of ourproportion of them reverted to normal when olanza- competitors are talking about a supposed linkpine was withdrawn. The fact that hyperglycaemia between hyperglycemia/diabetes and ZYPREXA.was reversible at least if caught early was not This is one of the biggest issues we face in theappreciated by one Eli Lilly company psychiatrist, marketplace. The exciting thing is that we havewho responded in an October 2002 email: “But, more data than ever to back up our story ofsurely we want patients to stay on OLZ long-term, so “comparable rates of hyperglycemia and diabetesthe reversibility of the event is not an advantage?” across psychotropic agents.” It is critical to our(Williamson 2002). success that we share this information with An internal email dated “12/01/98” on “Subject: physicians (Eli Lilly 2001b).Re: Wishing/Goldstein articles” stated: Internal documents addressed to sales reps mostly I do have concerns regarding making any refer to physicians, pharmacists and other health connections between olanzapine-induced weight professionals as “customers”. The September 2001 gain and hyperglycemia. Therefore, in my resource guide went on to note: “For tough customers, opinion, I would not include your following the use of the Hyperglycemia Sell Sheet followed by the statement: “Patients who gain weight may Study Comparison Insert increased the believability develop insulin resistance which may lead to of the ‘comparable rates’ message” and concluded: hyperglycemia and diabetes” (Kinon 1998). “Customers require lots of repetition for message By September 2000 Eli Lilly’s own market recall and true behaviour change”. Slides fromresearch revealed that many more physicians (81%) 2001, to be used in sales rep training reflected thatassociated “increased risk of diabetes with...Zyprexa” minimizing discussion of hyperglycaemia/diabetesthan with other agents—Clozaril (56%), Risperdal where possible was company sales strategy (Eli(16%), Haldol (11%), Mellaril (11%), Seroquel (7%), Lilly 2001b; see Figs. 6 and 7).Tercian (4%) (Phoenix International Research 2000).An internal email to 15 company scientists andexecutives from October 2000 on “Subject: meetingwith endocrinologic consultants” noted “at least thevocal” endocrinologists were disputing the company’s“finding that relative risk was not higher thancomparative drugs” and “reinforced (the writer’s)impression that hyperglycemia remains quite a threatfor olanzapine and may merit increasing even furthermedical attention and marketing focus on the topic”(Baker 2000). A reply email revealed a growing debatewithin the company “that unless we come clean onthis...issue that Zyprexa leads to diabetes...it could get Fig. 7 Excerpt from olanzapine sales representative trainingmuch more serious than we might anticipate” and urged material
Bioethical Inquiry A series of emails in March and April 2002 Quetiapine: Managing Side Effectsreveal that Eli Lilly was extremely keen to avoidregulatory product information label changes “to In a somewhat similar manner, data regarding weightnot use Zyprexa in patients with diabetes or a gain on quetiapine were managed by AstraZeneca.history of diabetes” and “contain a warning One internal document, titled “Seroquel Speakersstatement that some patients may experience a Slide Kit” from March 2001, was apparently utilizedmarked increase in blood glucose during Zyprexa to educate physicians regarding the safety andadministration” as proposed by Japanese regulators efficacy of the drug (AstraZeneca 2001). One slide(Cavazzoni 2002a, b; Kerr 2002). A verbatim makes the claim, in bold, that “Long-term Seroquelstatement was drafted on the issue that “Lilly’s has neutral effect on weight,” while another statedfundamental position regarding incidence of hyper- “Seroquel—weight neutral at all doses”. Several otherglycemia and/or diabetes across antipsychotic class slides make similar claims. These slides were basedcontinues to be ‘comparable rates’” and further that on studies examining the drug in the treatment of“Lilly stands by its science, and is exploring several schizophrenia. Another set of slides, included in aoptions to correct this regulatory injustice”. But the 2003 email, were said to “represent a core detailissue persisted and by November 2002 an email on flow” to “support our current position for Seroquel inthe Japanese label issue stated: “What is the strategy the treatment of schizophrenia”. One slide statedregarding diabetes? Are we trying to show through that: “Seroquel, unlike some other antipsychotics, isretrospective studies that it isn’t that big of a problem? I not associated with meaningful weight gain”understand that we are trying to neutralize the issue, but (AstraZeneca 2003).how are we trying to do that?” (Aubuchon 2002). On 15 Yet in July 2008, an internal analysis of quetiapineSeptember 2003 Eli Lilly “received letter from FDA studies in schizophrenia conducted from 1993 to 1999requesting inclusion of warning regarding hyperglyce- concluded that “the incidence rate in adult patientsmia and diabetes in labeling” for the US market (Eli with weight gain ≥7% in all trials was 18.2%” andLilly undated-f). that in placebo-controlled trials, the relative risk of By January 2004 the Eli Lilly “Weight Task clinically significant weight gain was 2.5 (Alam andForce” suggested “A major change in tone and Jeffries 2008). The document noted that “the resultsapproach is required (empathic with conviction) to of the analysis show that long-term treatment withrestore confidence...weight gain will no longer be quetiapine monotherapy was associated with moder-handled as an objection. Instead weight gain will be ate weight gain in patients with schizophrenia”.discussed up front, integrated into the brand However, a journal publication in 2000, with a leadpromise” (Eli Lilly 2004). Nonetheless a December AstraZeneca author, concluded that based on data2003 PowerPoint presentation for the sales reps from clinical trials with patients with schizophrenia,concerning “managing weight gain and diabetes quetiapine had a neutral effect on weight (Brecher etconcerns” suggested a less empathic approach (Eli al. 2000). A physician practicing EBM may haveLilly 2003; see Fig. 8). examined this study and concluded that quetiapine was weight-neutral when the internal data indicated that weight gain was a common side effect of the drug.1 Despite marketing claims to the contrary, employees at AstraZeneca were concerned about quetiapine- induced weight gain as early as 1997. In one email, written regarding an apparently fluke study associating quetiapine with weight loss, an employee noted that “we 1 One of the authors (PP) prescribed quetiapine to severalFig. 8 Excerpt from olanzapine sales rep training for managing patients due to its promotion as weight-neutral (based oncustomer (physician) concerns regarding weight gain and publicly available EBM at the time) and was quite surpriseddiabetes when some patients experienced significant weight gain.
Bioethical Inquirymust not get too carried away with weight loss when we episodes without inducing depression, acute depres-know the rest of our data appears to point in the other sion without inducing mania, and protect the patientdirection” (Hough 1999). In another email, a company from future episodes of mania or depression”. Thesephysician who worked with quetiapine noted that trial are noble aims but the same document indicated theresults consistently found that, over time, weight gain company did not yet have the data to support such a“doesn’t stop…the slope just appears to change” goal.(Arvanitis 1997). A brief synopsis of several relevant An internal company PowerPoint presentation ondocuments on the topic of quetiapine and weight gain “Zyprexa PCP [Primary Care Physician] Vision”is available online (Edwards 2009b). stated that a goal was to “Expand our market by redefining how primary care physicians identify, diagnose and treat complicated mood disorders (i.e.Disease Mongering Bipolar Disorder)” (Eli Lilly 2002b). A slide featured in Fig. 9 shows that the move into primary care was“Disease mongering” refers to the practice of expanding recognized as a challenge. Physicians in primary carethe recognised boundaries of a disease entity to did not typically treat bipolar disorder and usedencompass subclinical, borderline and normal range antipsychotic medications infrequently, partially duesymptoms in order to increase prescriptions and sales for to safety concerns. The company, however, aimed toa drug or therapy (Moynihan et al. 2002). Internal “change their paradigm”. Part of this marketingindustry documents concerning Eli Lilly’s atypical campaign was to broaden the concept of bipolarantipsychotic olanzapine (Zyprexa) suggest the com- disorder to include “complicated mood,” comprisedpany saw the potential to increase sales not only by of some combination of anxiety, disruptive sleep,gaining indication for the management of all phases of irritability, and mood swings (Spielmans 2009). Thisbipolar disorder, but for utilizing marketing tactics that new type of patient was a source of “untapped growthexpanded the boundaries of the illness itself. potential” for the drug. Additionally, fictional patient Eli Lilly’s original “lifeplan” document for olanza- vignettes were created for sales reps that highlightedpine in 1994 described the marketing profile for possible bipolar disorder or “complicated mood” inolanzapine as the “safer clozapine”; the market was to cases of relatively minor mood instability that did notbe schizophrenia and there was no mention of bipolar meet current diagnostic manual (DSM-IV, ICD-10)disorder (Eli Lilly 1994). However the company’s criteria for bipolar disorder I diagnosis. Thesepatent on its bestselling antidepressant fluoxetine vignettes were to be used in sales visits to help(Prozac) was due to expire in August 2001. Slides physicians identify patients who might suffer fromfrom a PowerPoint presentation at a meeting of the “complicated mood” symptoms. To handle objections“Zyprexa Product Team”, 25 July 2001, stated “The from physicians who indicated they did not treatcompany is betting the farm on Zyprexa. The ability schizophrenia or bipolar disorder, a script read:of Eli Lilly to remain independent and emerge as thefastest growing pharma company of the decadedepends solely on our ability to achieve world classcommercialization of Zyprexa” (Eli Lilly 2001c,italics in original). Graphs and text in the “ZyprexaProduct Team summary” from 1997 referring to“Global Zyprexa Bipolar Forecast” indicated salesprojections for the year 2000 would increase morethan fourfold if Zyprexa could be viewed as a“Depakote-like...MOOD-STABILIZER” rather thana “Risperdal-like...Antipsychotic” (Tollefson 1997).A slide titled “Bipolar Vision of Product Evolution”stated: “To be a leader in the bipolar market, Zyprexawill need to be viewed as a true mood stabilizer. A Fig. 9 Eli Lilly slide regarding perceptions of primary caretrue mood stabilizer will work in acute manic physicians toward bipolar disorder
Bioethical Inquiry“Doctor, would you agree that you see patients who “pharmaceutical company sponsored programs andpresent with symptoms of mood, thought, and tools in ‘fun’ environments”. They were also noted asbehavioural disorders who are not responding to your being highly responsive to discussions with salessatisfaction” (Eli Lilly undated-g). Thus, physicians reps, likely because High Flyers viewed reps aswho worked with exceedingly few patients who met “providing the source of latest information”. It wasdiagnostic criteria for olanzapine’s indications were also noted that they might like to become part of aencouraged to simply look for patients who had forum/club, presumably formed by the company, tosymptoms as opposed to the full-blown disorder in “reinforce NS [neuroscience] leadership in a socialquestion. way”. A skeptic might note that this technique could These documents, with reference to changing and be taking advantage of a certain vanity believed toexpanding the diagnostic paradigm for bipolar disorder, exist in the High Flyers, who would appreciate theirare of great topical interest in the context of the current “leadership” being recognized by a drug company.controversy over the boundaries of bipolar disorder To sell the exact same drug to a different group, the(Paris 2009). Despite valid concerns of late diagnosis “Rule Bounds,” a much different approach wasof bipolar disorder (Berk et al. 2006), there is evidence recommended. While the High Flyers did not playof overdiagnosis of bipolar disorder in recent years in by the rules, Rule Bounds were described as follows:adults (Goldberg et al. 2008; Zimmerman et al. 2008) & “I follow the rules when treating my patients; ifand children (Carlson 2009; Healy and Le Noury 2007; you don’t follow the rules, you’ll pay for it later”Moreno et al. 2007). It seems quite likely that & “Diagnosis clearly determined for treatment”pharmaceutical marketing is related to the increasing & “Wait to use medication when well established inrate of bipolar diagnoses (Zimmerman et al. 2008; the system”Healy 2006; Healy and Le Noury 2007). Rule Bounds were to be reassured that they were following treatment guidelines. It was advised thatMarket Segmentation Rule Bounds should be placed with physicians who could discuss “what everyone is doing”. It seemsThe lengthy Eli Lilly document titled “Key Player likely that the other physicians would be carefullyPlaybook” provides insight into how marketing selected by Lilly to make sure to describe olanzapine asmessages are tailored specifically to certain charac- the drug that “everyone” is prescribing, thus catering toteristics of a physician. Physicians were broken into the tendency of Rule Bound physicians to use “well-five segments: Rule Bound, High Flyer, Skeptical established” medications. Another document cited theExperimenters, Selective Majority, and Systematic company’s “superior recruiting capabilities so the rightConservatives (Eli Lilly undated-a). At the time the doctors go to the right programs,” then referencing bothdocument was written, olanzapine marketing was sales rep visits and “peer-to-peer” marketing, wherefocused on High Flyers and Rule Bounds. physicians would market the drug to their peers (Eli High Flyers were described as physicians who Lilly 2002c).were defined by the statement “I eagerly seek out new The other types of physicians (Skeptical Experi-ways to treat my patients (first to adopt new menters, Selective Majority, and Systematic Conser-medicines)”. These were the physicians on the cutting vatives) were perceived as less likely to respond toedge of medicine. Other descriptions of this segment marketing than Rule Bounds and High Flyers. Thus,of physicians were as follows: marketing resources were targeted toward the most easily influenced physicians, enabling Eli Lilly to& “Not bound by rules, guidelines, or system...” achieve a greater return on its marketing investment.& “Treat based on symptoms, not formal diagnosis”& “Will push the envelope with off-label doses and indications...” Potential Remedies Based on this profile, olanzapine marketers wereencouraged to utilize a few specific tactics to sell the MBM likely leads to poorer outcomes and increaseddrug. It was noted that High Flyers like to receive costs. The time is ripe to reform how data from
Bioethical Inquirypharmaceutical trials are disseminated. Clearly, better Conclusionaccess to raw data is needed. Clinical trial registrieshave not solved the problem; even among trials which Internal industry documents allow a glimpse into theappear in such registries, selective reporting of shadowy world of MBM, where data serve the needs ofoutcomes is common (Mathieu et al. 2009). Editors, marketing and inconvenient data are often recast aspeer reviewers, and readers of trial results should positive or buried entirely. If, on the other hand, we are tocheck online registry entries to verify whether the fulfil the worthy ambitions of EBM, all data collected indata in a published clinical trial match the results and clinical trials would be easily accessible. Journal articlesprotocol in the registry. In addition, public access to would accurately represent the underlying data andregulatory agency reports would also be useful, as individual contributors to a study would be given creditthere is often a notable discrepancy between data for their role in conducting research. Marketing effortsreceived by regulatory agencies and data published in would contain accurate information. However, in themedical journals (e.g., Turner et al. 2008a). Public current world of MBM, journal articles are an overlyaccess to both trial protocols and results would greatly positive representation of safety and efficacy, articles areincrease transparency and allow physicians and often prepared by drug marketers (whose influence isconsumers to better assess the validity of clinical trial hidden by honorary authors), marketing efforts containresults (Chan 2008). misleading information about both diseases and treat- More radical methods have also been proposed. ments, and physicians are partitioned into market seg-A former editor of BMJ, Richard Smith, suggests ments in order to best persuade them to believe variousthat journals should cease the publication of clinical marketing pitches. Until such issues are resolved,trials. Rather, trial protocols and results could be particularly those regarding widespread access to accu-published in some form of online registry. Journal rate data, any great enthusiasm for so-called evidence-articles would then discuss the validity of these based medicine should be viewed with scepticism.trials. This may seem like an odd solution, butthere is in fact little evidence that peer review islinked with notably better reporting of trial results Limitations(Jefferson et al. 2007). Reprints of trials withostensibly positive results are often disseminated to The industry argues in court that subpoenaed documentsprescribers, a marketing strategy that one large are taken out of context. This should be considered bybiomedical journal publisher calls “invaluable for readers of the above excerpts. A fuller picture is availabledirect marketing, exhibitions/seminars, sales cam- from reading the many documents released and postedpaigns, and for mailing new product information to on the internet (e.g., http://www.furiousseasons.com/physicians” (Elsevier 2007). Further, reprints generate zyprexadocs.html, http://www.furiousseasons.com/revenue for journals; thus, Smith claims that editors may zip/seroqueldocs.zip, www.healthyskepticism.org/feel pressured to publish trials that could make profits documents/Antipsychotics.php). However, having readfor the journal’s publisher regardless of the trial’s quality through hundreds of such documents the authors found(Smith 2005). Indeed, Smith estimated that one little to contradict and much to support the conclusionsespecially profitable reprint used to market the now proffered here.disgraced painkiller rofecoxib generated about$450,000 for the publisher (Smith 2006). Such Acknowledgements The authors wish to acknowledge theconflicts of interest could be eliminated if journals no work of journalist, Philip Dawdy, who has written much onlonger published clinical trials. However, it seems these documents and whose website www.furiousseasons.com is one of the main hosts of internal industry documents. We alsounlikely that publishers would want to reduce their recognize the work of journalist Jim Edwards (http://industry.profitability by simply giving up publication of clinical bnet.com/pharma/blog), who has written much about several oftrials. These reforms may seem drastic, but if we are the documents discussed in this paper.truly interested in providing the most safe and effective Disclosures Glen I. Spielmans has holdings of less thantreatments to patients, then the actual scientific $10,000 in a mutual fund (Vanguard Health Care), whichevidence regarding treatments must be made publicly invests nearly exclusively in pharmaceutical companies. Dr.available. Parry is a member of Healthy Skepticism.
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