health economists meet the fourth tempter: drug dependency and scientific discourse

HEALTH ECONOMICS

Health Econ. 9: 659–667 (2000)

GUEST EDITORIAL

HEALTH ECONOMISTS MEET THE FOURTHTEMPTER: DRUG DEPENDENCY AND

SCIENTIFIC DISCOURSE

STEVE MORGANa, MORRIS BARERa,b,c,* AND ROBERT EVANSa,c,d

a Centre for Health Ser6ices and Policy Research, Uni6ersity of British Columbia, Canadab Department of Health Care and Epidemiology, Uni6ersity of British Columbia, Canada

c Program in Population Health, Canadian Institute for Ad6anced Research, Canadad Department of Economics, Uni6ersity of British Columbia, Canada

I am only here, Thomas, to tell you what youknow . . . Save what you know already, ask nothingof me (Fourth Tempter). T.S Eliot, Murder in theCathedral.

More than any other time in history, healtheconomists face a crossroads . . . Let us pray wehave the wisdom to choose correctly (with apologiesto Woody Allen).

Over the past decade, the ‘pharmacoeconomics’phenomenon has incited a stream of commen-taries about the economic evaluation of drugs,conflicts of interest and ways of retaining re-spectability for this component of the health eco-nomics profession [1–10]. Private corporationsnow finance so many aspects of health economics,however, that the profession as a whole runs therisk of being co-opted. As Maynard and Kanavosrecently pointed out, there has been such a flurryof activity around pharmacoeconomics that out-siders often assume health economics and eco-nomic evaluation are synonymous [11].

It would seem self-evident that carrying outmicro-evaluations of new drugs at the behest of(and financed by) the originating industry is notthe most socially valuable use of our profession’stime, however rewarding it may be for particularindividuals. Though some relationship betweenthe profession and industry may be a regulatory

necessity, the scale and scope of the pharmaceuti-cal sector’s investment in health economics speaksof something else. Investments by drug companiesin any aspect of the health economics profes-sion—from research projects to academic chairs,to professional associations and journals—arebusiness decisions. Our own economic models canbe used to predict their outcome. And if (Godforbid) we doubt the applicability of our theoreti-cal apparatus, we need only turn to the experienceof the clinical sciences for evidence supporting itspredictive power.

Standard economic theory postulates that thebehaviour of private firms is driven by the objec-tive of profit maximization. According to theFortune 500 industry medians, pharmaceuticalmanufacturing has been the most profitable in-dustry (in terms of median return on equity, salesor assets) in 11 of the past 14 years. Perhaps drugcompanies are just inherently profitable, regard-less of what motivates their managers, benefitingfrom a fortuitous combination of industry andmarket characteristics. A more reasonable expla-nation, however, is that this persistent and stellarprofitability results from the determined andskilful pursuit of precisely the objective postu-lated by economic theory: profit-maximization.After all, if these profits were a happy but slightly

* Correspondence to: Centre for Health Services and Policy Research, University of British Columbia, Vancouver, BC, CanadaV6T 1Z3.

Copyright © 2000 John Wiley & Sons, Ltd.

S. MORGAN ET AL.660

embarrassing accident, drug companies could al-ways lower their prices.

With extraordinarily high fixed costs and lowvariable costs of production, the route to prof-itability for drugmakers is through sales. And,indeed, pharmaceutical firms spend more on mar-keting than they do on research [12,13]. At leastpart of the selling process in the pharmaceuticalindustry involves the creation and disseminationof scientific evidence concerning the merits of aproduct. In an ideal world, corporate investmentin clinical research would facilitate prescriptiondecision-making based on objective evaluations ofhard scientific evidence regarding safety, efficacyand cost-effectiveness. Reality, alas, intrudes.

Pharmaceutical companies are not educationalcharities, participating in disinterested productevaluation. They are not much interested in thepursuit of scientific understanding for the greatergood. Science and objectivity are of interest to aprivate, for-profit corporation only insofar as theyfurther the quest for profits. In fact, to the dis-comfort of many economists, economic theorydoes not rule out the destruction of scientificinformation or the production of false informa-tion as a means of pursuing the profit objective,just as it does not rule out the contamination ofthe environment, the use of child labour or thesale of known carcinogens. Consider, for example,the long and sordid history of the tobacco indus-try. The analyst may annex a side-assumptionthat such behaviour is, for some reason, unprof-itable, but the theory includes no suchpresumption.

The premise that firms maximize profits is notnormative; it is merely an intuitively plausiblemodelling assumption used as a basis for gener-ally successful predictions about firm behaviour.Profit maximization may result in ‘ethical’ be-haviour, provided that regulators and/or con-sumers detect and punish ‘unethical’ behaviourwith sufficient frequency and severity to render itunprofitable. When undetected and/or insuffi-ciently penalized, behaving badly can be goodbusiness. Failure to accept this proposition re-quires one to jettison the standard theory of thefirm and come up with some other theory ofmotivation for predicting firm behaviour.

In the pharmaceutical sector, it may be prof-itable for a firm to promote bias in the creation,evaluation and dissemination of information so asto encourage sales—again, provided that such

behaviour is either undetected or carries penaltiesthat are outweighed by its profit potential. Thepicture that has emerged from the clinical sciencesoverwhelmingly suggests that such ‘unethical’ be-haviour is, in fact, profitable because it is found ina number of routine business practices in thepharmaceutical industry [14].

Despite scientific pretences, drug companieshave injected various forms of bias into virtuallyevery aspect of the product evaluation process.They begin at the front lines, with the courtshipof the practising physicians who are responsiblefor choosing drugs on behalf of individual pa-tients. The most notorious business practice inthis respect is gift-giving. Gifts bestowed uponphysicians yield the sponsoring firm (and its prod-ucts) favourable emotive exposure that has noth-ing to do with objective scientific information.Complimentary meals, travel, gifts and entertain-ment all have a documented impact on prescrib-ing, increasing the use of the sponsor’s productsregardless of appropriateness [15,16]. As eco-nomic theory might predict, gifts and incentivesare geared to the physician’s response. ‘Heavyprescribers’ are identified and courted with partic-ular favour, and emphasis is placed on getting todoctors while they are still in medical school. (Theimportance the pharmaceutical industry places onaccess to impressionable medical students hasbeen revealed by its ruthless reaction to attemptsat limiting this access [17].)

Of course, not every physician accepts gifts andnot all of those who accept them are influenced.Even those physicians most likely to believe theclaims made by drug manufacturers will also beinfluenced by other sources of information aboutthe safety and efficacy of a product. For, alongwith other potentially competing interests, thephysician’s primary fiduciary duty is to the pa-tient. But, if gifts and other inducements did notaffect prescribing behaviour, economic theory(and common sense) predicts that they would notbe offered.

Medical associations, which play a major rolein upholding the professional standards of careamong their members, have long been a third-party source of information for prescribing physi-cians. They sponsor educational seminars andpublish journals and newsletters that providedrug-related information. Prescribing informa-tion, cautions, and guidelines disseminated underthe auspices of medical associations carry the

Copyright © 2000 John Wiley & Sons, Ltd. Health Econ. 9: 659–667 (2000)

DRUG DEPENDENCY AND SCIENTIFIC DISCOURSE 661

implicit scientific credibility that professional en-dorsement brings. Consequently, having productspromoted through—and implicitly endorsedby—the medical associations may be of signifi-cant value to manufacturers. Pharmaceuticalmanufacturers have accordingly invested tremen-dous resources in marketing activities that arechannelled through medical associations. In theprocess, drugmakers have allied the medical pro-fession as a whole, just as they have allied individ-ual physicians.

Through grants, advertising and other sourcesof financial support, medical associations areheavily reliant on the pharmaceutical industry asa source of funding. Despite the fact that virtuallyevery systematic review of the content and impactof drug advertising confirms that it is of dubiousinformation value [16,17], the financial gains frompermitting advertising have proved too strong forassociations and their journals to resist. Drugadvertising in major medical journals generatesmore revenues for professional associations thatpublish them than do fees and levies on members[18]. These revenues place the associations in anobvious conflict of interest [19,20].

Also through medical associations, drug com-panies fund continuing medical education pro-grams, consensus conferences, scientific meetings,and the development of prescribing guidelines.Educational grants given to finance these activi-ties—even if ‘unrestricted’—influence the deci-sions of those designing and implementing theprograms [21]. As economic theory would predict,the result is that educational events systematicallyfavour the sponsor’s products [19,21,22].

The argument that profit motives can actuallyinfluence the process, and thus, the outcome, ofscientific inquiry may appear more controversialthan the rather mundane observation that corpo-rations will put ‘spin’ on scientific findings topromote their interests. Yet, the theory of the firmmakes no distinction between the two. If invest-ments in clinical sciences can be orchestrated in away that generates favourable findings, which, inturn, generate more sales, economic theory pre-dicts that firms will so orchestrate their invest-ments. To the extent that corporations canemploy soft or non-scientific methods to generate‘positive’ findings without being detected or (suffi-ciently) punished, for-profit firms will choose fa-vourable results over scientific integrity.

Using financial, contractual and legal means,drug manufacturers retain a degree of controlover clinical research that is far greater than mostmembers of the public (and, we suspect, manymembers of the research community) realize.There are numerous mechanisms through whichthe scientific evidence generated in a clinical studycan be biased by the sponsoring corporation [23].Drug companies commonly control the researchquestion (with what products and what doses, andfor what patients and conditions, is the new drugcompared?), they control the selection of patientsfor the trials, they control how drop-outs andside-effects are reported and treated in the analy-sis, and they control what information makesits way into scientific presentations and peer-reviewed publications. Drug companies often usesurrogate endpoints to establish a product’s effi-cacy (and to establish a market for the product),despite absence of evidence that the surrogateoutcome and health status are in fact correlated,and sometimes, in the face of evidence that theyare not [24,25]. Industry-funded trials are typicallyconducted on populations that are younger andhealthier than the patients for whom the drug willbe prescribed in practice. And finally, when man-ufacturers fund head-to-head drug trials to illus-trate comparative efficacy, they often choosequestionable products, dosages or forms of ad-ministration as the comparators against whichtheir drugs are tested [23,26,27].

This industry control over the evaluation pro-cess has documented effects on both empiricalfindings and expert opinions. Drug company-funded clinical trials are more likely than non-industry funded trials to generate ‘scientific evi-dence’ that favours the funding company’sproduct, and the scientific data are more fa-vourably interpreted by those with financial tiesto related drug companies [28]. Stelfox and col-leagues, for example, found that 96% of the au-thors who supported the continued use ofcalcium-channel blockers, despite uncertainty con-cerning their safety, had financial ties to manufac-turers of calcium-channel blockers [29]. Incontrast, only 37% of authors who raised orechoed concerns about the potential risks posedby calcium-channel blockers had such financialties.

Drug companies are also very careful aboutwhat aspects of their studies reach the publicdomain, so no one outside the corporate veil ever


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sees the entire evidentiary picture [30,31]. As theclinical data generated by industry-funded drugtrials are proprietary, being the product of costlyresearch investments, they are seldom open tocompetitive or public scrutiny. Secrecy, however,is the antithesis of good, transparent science. Itnot only undermines the external-review processesfor studies that are ‘made public’, secrecy alsoengenders reporting biases. Most manufacturersrefuse to pre-register their clinical trials, so thatauthors of review articles will not know when astudy has been abandoned as a result of unfa-vourable findings [26,31]. Moreover, positive re-sults of industry-funded studies are frequentlypublished multiple times (often with different au-thorship and no cross-referencing) to create afalse impression of independent confirmation andweight of evidence [27,31]. The evidentiary pictureput before the public is far more rosy than theactual experiences of test subjects would suggest.

Hospitals and universities have too often tacitlyacquiesced to these practices by permitting con-tract-based research on terms directly inimical togood science and patients’ interests [32]. It shouldnot be surprising, in a time of declining publicfunding, that universities and hospitals are willingto accept research contracts with strict disclosureand confidentiality clauses and/or methodologicalflaws. Pharmaceutical companies are majorsources of revenue, upon which hospitals anduniversities have come increasingly to depend. Inaddition to fees paid on contract for specificstudies, drug companies frequently give large do-nations or corporate grants to public institutions.These for-profit firms do not engage in hand-outswithout reasons tied, directly or indirectly, backto the corporate bottom line. Gift-giving to publicinstitutions by drug companies raises a company’simage and serves as a means through which theycan influence the decisions of universities andhospitals. Widely noted cases of public institu-tions bowing to the pressures of drug companyinfluence include those of Dr Betty Dong of theUniversity of California at San Francisco and DrNancy Olivieri of the Hospital for Sick Childrenin Toronto [33–36]. In both cases, drug compa-nies attempted to block the publication of unfa-vourable study results. To protect corporaterelations—and the flow of future grants and do-nations from the study sponsors and other drugcompanies—the academic institutions withdrewlegal support for their researchers at critical

points in both cases. Following prolonged attackson their methods and analyses—and on the re-searchers themselves—both studies were eventu-ally published in peer-review journals.

Legal threats, regardless of their merit, are in-creasingly being used as a means by which thedrug industry silences recalcitrant researchers[36–39]. Whether or not successful at trial, law-suits raise very significantly the expected costs ofconducting and publishing clinical research thatyields results ‘unfriendly’ to the objectives of man-ufacturers. The individual researchers under legalattack may win in the courts, but they lose con-siderable time, energy and money, and are put ata disadvantage in research competitions with theirpeers [36]. Other researchers note this. It is hardto gauge how much critical research is ‘chilled’ asa result, but such chilling is a plausible companyobjective—‘punish one to teach a thousand’.

Legal actions are launched not only againstthose who conduct clinical research, but alsoagainst those who conduct evaluations and pub-lish clinical guidelines. In 1997, Bristol-MyersSquibb sued the Canadian Coordinating Office ofHealth Technology Assessment (CCOHTA) toprevent release of a summary report on drugsused to lower blood cholesterol. They were unsuc-cessful at trial, and on appeal, but effectively shutdown CCOHTA for a year and drained its bud-get. Meanwhile, they continued to exploit theirleading market position. The additional revenuesundoubtedly more than covered their legal ex-penses. In 1998, Astra-Zeneca had its lawyersthreaten legal action against McMaster Univer-sity’s Dr Anne Holbrook, who had chaired acommittee for the Government of Ontario toevaluate guidelines for the treatment of pepticulcer disease and reflux. The company was notsatisfied with the panel’s findings, and wanted thereport suppressed, and so threatened Dr Hol-brook personally [40]. Three German pharmaceu-tical companies, supported by the PharmaceuticalIndustry Association, successfully suppressed thepublication of a 1997 report that listed therapeu-tic alternatives to unproven medicines. Ironically,the Association argued in the courts that thereport was biased because several leading in-surance companies provided financial assistanceor data used in the analysis of the alternativeproducts! A spokesperson for the Association,Kerstin Kilian, argued that ‘[t]his is not an inde-pendent body that’s putting this book out, andit’s not as scientific as it appears’ [41].



What is certainly not scientific—in appearanceor otherwise—is the emerging trend toward drugtrials designed, managed and reported by privatecontract research organizations. In 1991, aca-demic centres accounted for 80% of industry-funded clinical trials; in 1998 they accounted foronly 40% [42–44]. Private contract-based researchfirms picked up the difference. The ostensiblereason for the change in research settings is thatprivate firms can conduct research more quicklythan universities and hospitals. This is clearly ofinterest to firms who wish to get the maximumnumber of market days out of their fixed-termpatents. However, a secondary advantage of con-tract research is that the firm can retain completecontrol over questions, methods, data and publi-cations, without any hindrance from academicreview processes or ethics committees. While aca-demic researchers and clinicians may still be in-volved in the research, no one of them will have asufficient grasp of the overall project to be able toquestion methods or early warning signs, or toexamine the incoming data from all participatingcentres.

Many studies conducted by for-profit researchorganizations are, in fact, commissioned and or-ganized by the firms’ marketing departments, nottheir regulatory/scientific departments, after thedrug has already been approved for sale. These‘seeding studies’ are purely for promotional pur-poses, the regulatory hurdles having already beenpassed. In addition to generating clinical data quapromotional material, they give marketers directaccess to individual prescribers and patients, plac-ing the new drugs in their hands and encouragingtheir use for ‘scientific’ purposes.

Professional medical writers frequently write upresults of privately contracted clinical research.The articles are published under the names ofprominent researchers or clinicians paid a fee forreviewing the manuscript and attaching theirnames to the publication. The practice of ghost-written articles being published under honorarymultiple authorships has become so pervasive,and the belief that this reduces accountability forresearch is so strong, that some medical journalsnow require that authors list their contribution tothe research [45].

Having for-profit organizations conduct re-search on behalf of pharmaceutical companies,and public relations firms coordinate the publica-tion and put media ‘spin’ on results, completes the

process by which the industry has infiltrated everystage of the modern research enterprise. Facedwith this infiltration or envelopment, patient wel-fare and scientific process are simply over-whelmed by the profit objective of thepharmaceutical companies. Bringing it right backto the front lines, private practitioners have be-come more than willing pawns in this process,often putting their own financial and academicinterests ahead of the interests of their patients. Inthe private contract-based research setting, datagathering is conducted by ordinary practisingphysicians [42–44]. The fees paid for enlistingpatients in these studies, combined with bonusespaid for meeting recruitment targets and dead-lines, can amount to hundreds of thousands ofdollars per year [44]. The notion of supplier-induced demand takes on a whole new complex-ion in this context. Inappropriate treatment oc-curring under heavy financial incentive for patientenlisting appears to be a form of ‘collateral dam-age’ acceptable to the physicians, contract re-search organizations and funding drug companies.

Contract research for profit is a recent develop-ment, but all the other marketing practices de-scribed above are decades old. Documentation ofendeavours to generate biased clinical evidencefor marketing purposes dates back decades. Asearly as the mid-1950s, public commissions ofinquiry in Canada, the US and the UK all re-ceived testimony of industry efforts to introducebias into the prescribing process, not only by theubiquitous practice of giving gifts and other bene-fits to prescribing physicians, but through financ-ing articles in journals intended for prescribingdoctors, and influencing their content [46–48].Then, as now, drug companies sponsored drugtrials; hand-picked investigators depending on thedegree of quality needed (e.g. picking young in-vestigators of little or no reputation to study themore dubious me-too drugs); discouraged thepublication of unfavourable results; used multipletrials at different centres to raise awareness for adrug prior to its market launch; and publishedresults multiple times (both pre- and post-launch)so as to hamper those searching for scientificevidence. As Yale political scientist Ted Marmorhas noted, ‘Nothing that is regular is stupid’.These practices are profitable.

In light of the extent to which the drug industryhas co-opted the research system that is supposedto serve the purposes of clinical evaluation and,


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ultimately, patients, it is difficult to determinehow scientifically valid most of those evaluationsare. This poses a dilemma for those engaged ineconomic evaluations of medicines, because eco-nomic evaluations are often based on or run inparallel with clinical trials that are subject to themany sources of industry influence noted above[3]. It also poses a dilemma for the health eco-nomics profession more generally. If the drugindustry, with its global economic influence, hasmanaged to gain financial leverage on virtually allaspects of the clinical and clinical research profes-sions relevant to the marketing of its products,what is preventing it from doing the same to/withthe economics profession?

In fact, the pharmaceutical industry is already amajor investor in health economics, and the pat-tern of infiltration and take-over that is emergingis, in the words of that distinguished literaryscholar Yogi Berra, ‘deja 6u all over again’. Drugcompanies do not court economists to the sameextent that they do practising physicians, norwould economic theory predict that they would.Drugmakers court individual practitioners quaconsumption decision-makers. Economists, afterall, prescribe no drugs to patients. (And a goodthing too!)

But they do prescribe policies to governments.And drug companies have, in recent years, be-come major sponsors of professional organiza-tions of health economists and of professionaljournals to which health economists contribute.Pharmaceutical companies account for almost onequarter of the revenue base for the InternationalHealth Economics Association—similarly for theCanadian Health Economics Research Associa-tion. Fifty-eight percent of the members of theInternational Society for Pharmacoeconomics andOutcomes Research are not university-based re-searchers, but employees of the drug industry orof private research organizations. Approximatelyone quarter of all job postings in iHEA News(published by the International Health EconomicsAssociation) are for positions at drug companiesor with private for-profit research and consultingfirms. Moreover, increasing numbers of privatefor-profit companies (many with high-profile aca-demic researchers as principals or sitting onBoards of Directors) are specializing in servingthe evaluation needs of drugmakers.

As economic models involve numerous assump-tions that are subjective and often subtle, they are

particularly susceptible to bias driven by conflictsof interest [49]. Trends in the marketplace foreconomic research, and published evidence, sug-gest that such bias is present. Regardless of fund-ing source, published pharmacoeconomic studiesgenerally provide methodological disclosure thatmeets the ‘test’ of common evaluation guidelines(e.g. whether authors identified the study perspec-tive, adequately described the study objective,design, and results) [50,51]. However, those guide-lines leave ample scope for reporting variationand creativity. For example, a study that adoptedan inappropriate comparator or whose samplingwas biased could, nevertheless, easily pass the‘acceptable reporting’ threshold if readers weretold what the comparator was, and how the sam-pling was done. There is, furthermore, a correla-tion between funding source and favourability ofpublished results. Among published pharma-coeconomic evaluations, those that are industryfunded are more likely to report favourable find-ings and tend to contain more qualitative over-statements of the results than those sponsored bynon-profit organizations [52]. Moreover, between1988 and 1994, results favourable to the drugunder evaluation were found in a remarkable 92%of all drug evaluation studies published in Phar-macoEconomics—the for-profit journal dedicatedto publishing economic evaluations commissionedby its editors and Editorial Board. Eighty-threepercent of the drug evaluations in PharmacoEco-nomics were funded by the pharmaceutical indus-try. By contrast, the rate of positive findings was30% in similar studies reported in the New Eng-land Journal of Medicine, which has among thestrictest conflict of interest policies for economicevaluations [53]. Finally, when submitting evalua-tions required by regulation, manufacturers (orthe authors who write on their behalf) tend tointerpret clinical data more favourably than regu-lators [54].

Plausible explanations or justifications thatmight relieve individual and collective consciencesof health economists could, given sufficient cre-ativity, be found for all of these observations. Butit is inconsistent for us as economists to pretendthat funding from drug companies has no impacton research. Economic theory predicts that con-tracts offered by firms will be designed in such away as to guide the agents’ behaviour in a mannerbest suiting the firms’ objectives, subject to theparticipation constraint. Successful corporations



do not repeatedly make mistakes (‘nothing that isregular is stupid’); and pharmaceutical corpora-tions are among the most successful. If gifts andgrants to health economists, their research units,their host academic institutions, professional asso-ciations, and private consulting firms did notinduce a behavioural response that would other-wise not occur, then firms would cease to providesuch ‘support’. Industry funding of health eco-nomics will influence what questions are asked,and how, just as it has done in clinical research.To believe otherwise is to ignore not only thegrowing (and worrying) body of evidence fromthe clinical research world, but also the implica-tions of our own economic theory of firmbehaviour.

AND SO . . .

As regulatory and purchasing arrangementsacross the industrialized world have made eco-nomic evaluation of new drug products virtuallymandatory, health economists have found them-selves in an enviable market position. Drug com-panies need a steady stream of new licensedproducts to continue to grow at rates that share-holders have come to expect. Getting new prod-ucts through that pipeline requires the input ofeconomic analysis at key points in the process.But it also requires the ‘right’ results from thisanalysis. This has meant a need to find ways ofengaging health economists in the pursuit of in-dustry goals. Luckily for the industry, there aretechniques for researcher co-optation alreadytested and very successfully proven in the clinicalresearch environment.

In the absence of concerted counter-measuresby health economists, many in our profession willbe led down the path taken by so many clinicalresearchers. Moreover, we can be equally certainthat the industry will seek to penetrate and drawthe teeth of any insurgency we do orchestrate—the empire will strike back! Thus, instead of therelatively rigorous auditing process suggested byReinhardt [6], attention has been focused on‘guidelines’ for economic evaluation that areweak, vague, and voluntary (and seldom followed[54,55]). Indeed, this weakness serves the interestsof economists as well as those of the industry, asit assures a continuing need for our expertise and‘professional judgement’.

This raises a much more fundamental issue. Areeconomists themselves simply income maximizers?(Or rather, are we utility maximizers with a sub-stantial weight, at the margin, on income?) Ourown theories might suggest as much. If so, thenour evolving relationship with the industry is fore-ordained. But if we have pretensions to a highercalling, then we have some tough choices to make,individually and collectively. Or not. . . but if not,the choices will be made for us.

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health economists meet the fourth tempter: drug dependency and scientific discourse

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