Egger, M.

Fey, MF

Jüni, P.

Trelle, S.

Wick, C.

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The characteristics of unsolicitedclinical oncology literatureprovided by pharmaceuticalindustryThe pharmaceutical industry plays an important role in thedevelopment of new cancer treatments. Data from clinicalphase I to III trials will, if convincing, eventually lead tothe licensing of the drug. At that stage, and even before,companies embark on marketing and promotion of theirnew products [1, 2], by advertising in professional journals,through visits by drug company representatives, theorganization of promotional meetings or sponsoring ofcontinuous medical education. Finally, many drugcompanies maintain promotional mailing services tophysicians to provide them with regular information,particularly on new drugs. Concern has been voiced thatadvertising may lead to uncritical and inappropriateprescribing of new drugs in clinical practice [3]. Articlesprepared with drug company support have been shown tobe more likely to report favourably on a drug of interestthan articles published without such support [4]. Inadvertisements for antihypertensive and lipid-lowering drugsin Spanish medical journals, the promotional statement wasnot supported by the studies cited in 40%, most frequentlybecause the advert recommended the drug in a patient groupother than that assessed in the respective trial [5]. Drugcompanies may exert a considerable influence over whichdrugs doctors prescribe [6], and also influence continuousmedical education. A recent letter to the Annals of Oncologypointed out that visits of pharma representatives in clinicaldepartments are increasing apparently with the aim ofpushing clinicians towards using their specific drugs [7–9].Whereas the relationship and interactions between doctorsand drug company representatives and the advertisingpractices of industry have been examined in several studies[5, 10, 11], promotional mailings have not been analysed indepth. We studied the characteristics of literature and othermaterial mailed by the pharmaceutical industry to a medicaloncologist in Switzerland.One of us (MFF) prospectively and comprehensivelycollected all unsolicited mail posted to his hospital addressfrom pharmaceutical companies from 1st January to 30thSeptember 2002. We classified the material as follows: (i)peer-reviewed journal articles (reprints of original researchor reviews), (ii) abstracts from peer-reviewed articles, (iii)customized abstracts, (iv) lists of references and (v)publications prepared by industry or communicationletters to the editor Annals of Oncology1580 | letters to the editor Volume 18 |No. 9 | September 2007companies working for industry. The latter consisted ofnewsletters or conference reports, for example editorialswritten by opinion leaders, reviews prepared by industry andinterviews with keynote speakers. Abstracts published injournals or conference proceedings that had been rewrittenor edited by industry were classified as customized abstracts.We assessed whether in material reporting on clinical trialsof anticancer drugs, results were interpreted as showingsuperiority or inferiority of the new drug, or no differencebetween comparison groups. Statements such as ‘‘newtreatment offers significant improvement over .’’, ‘‘newdrug significantly better .’’, etc. were interpreted asindicating superiority.Forty-nine mailings including a total of 961 items from 13different pharmaceutical companies were received during thestudy period (1.25 mailings and 24.6 items per week). Thevast majority of items received were customized abstracts(768, 80%; Table 1). Thirty items were original abstracts(3%) and seven (0.7%) were reprints of articles published inpeer-reviewed journals. A total of 156 items (16.3%) werefrom industry newsletters or conference reports. Among the805 items selected from the literature and conferenceproceedings, reports on clinical trials (276 items, 28.7%) andnarrative review articles (271 items, 28.2%) were mostcommon. Among clinical trials, phase II studies (125, 46%)were more frequently included than phase III (95, 34%) andphase I studies (56, 20%). Only 12 (1.2%) items reported onsystematic reviews. The drugs most frequently examined inthe 220 phase II and phase III studies were tamoxifen,anastrozole and docetaxel. Head-to-head comparisons ofdifferent drugs were reported in 120 (55%) items (86 phaseIII and in 34 phase II clinical trials). The remaining articlescompared different dosages of the same drug in dose-findingstudies or the effect of different numbers of treatment cycles.A total of 173 reports of phase II and III trials (79%)reported results that favoured the drug produced by thecompany responsible for mailing the item (Table 2).Most of them reported unpublished data from meetingabstracts.Although our study was based on the mail received by oneSwiss medical oncologist, we assume that the material wasrepresentative of what was mailed to many, if not all,practising oncologists in Switzerland during the samplingperiod as a part of mass mailings. Mailings were frequentand mainly included abstracts of unpublished studiespresented at conferences, which were often edited (customized)by industry. Clinical trials and narrative reviews dominated,whereas systematic reviews were virtually absent. Amongphase II and phase III drug trials, a large majority of itemsreported results that were favourable to the drug producedby the company sending the material. An interesting findingof our study is the frequent use of customized, rewrittenor edited, abstracts. Their content was often simplified,and data presented in more appealing ways, for exampleby using colour graphs rather than tables. Clearly, furtherresearch is needed to clarify whether and in what waycontent and conclusions may have changed in this process.Many practising physicians value promotional efforts ofpharmaceutical companies to communicate data on newdrugs with possible relevance to their daily clinical work.Company-based promotion is highly organized andallegedly comprehensive, as evidenced, for example, by theinclusion of reference lists in the mailings examined in thisstudy. The selection of the abstracts included in themailings maywell have favoured the company’s drugs, similar to the well-documented selective publication of positive results [12].Furthermore, the majority of the items related to conferencepresentations of unpublished studies. Meeting abstractsrepresent preliminary, immature and incompletecommunications of clinical data. Their validity is therefore lowerthan that of peer-reviewed original articles published in scientificjournals [13]. The conclusions published in meeting abstracts donot always match the conclusions from the correspondingoriginal article that is typically published in peer-reviewedjournals 1–2 years later. Finally, unsystematic narrative reviewsof published evidence often reach erroneous conclusions, andsystematic reviews and meta-analyses, which are based oncomprehensive literature searches and careful assessment of thequality of component studies are more reliable [14]. The clearfocus on narrative reviews in the material sent to oncologistsTable 1. Types of studies and articles selected by industry for mailingfrom the literature and conference proceedingsDesign Type of articlePeer-reviewedjournalarticleOriginalabstractCustomizedabstractTotalClinical trial 2 27 247 276 (28.7%)Phase I 0 6 50 56Phase II 1 16 108 125Phase III 1 5 89 95Narrative review 2 2 267 271 (28.2%)Systematic review 0 0 12 12 (1.2%)Cohort study 2 0 67 69 (7.2%)Case–control study 0 0 28 28 (2.9%)Case series 1 1 85 87 (9.1%)Case report 0 0 28 28 (2.9%)Laboratory study 0 0 22 22 (2.3%)Economic study 0 0 12 12 (1.2%)Subtotal includingscientific articles7 (0.7%) 30 (3%) 768 (80%) 805 (83.7%)Total 961 (100%)Table 2. Conclusions from phase II and III drug trials selected byindustryType of trialPhase II Phase III TotalExperimental drugLess beneficial 8 (6.5%) 11 (11.5%) 19 (8.5%)More beneficial 105 (84%) 68 (72%) 173 (79%)Equivalent 8 (6.5%) 11 (11.5%) 19 (8.5%)No clear statement 4 (3%) 5 (5%) 9 (4%)Total 125 (100%) 95 (100%) 220 (100%)Annals of Oncology letters to the editorVolume 18 |No. 9 | September 2007 letters to the editor | 1581must therefore be of concern, and represents another potentialsource of bias.We found that 80% of clinical trials were interpreted asshowing superiority of the drug produced by the companymailing the item on the trial. In addition to the selectiveinclusion of positive studies, the inclusion of trials of lowmethodological quality, which tend to exaggerate effects, isanother element of concern [15, 16]. Trials may be designedto produce positive results, for example by usingcomparison treatments that are known to be substandard.Such trials violate the uncertainty principle: patientsshould be enrolled in randomized clinical trials only, ifthere is substantial uncertainty about the efficacy of thetreatments being compared. A recent survey of randomizedclinical trials in patients with multiple myeloma [17] foundthat overall the uncertainty principle was upheld, with 56%of trials favouring experimental treatments and 44%standard treatments. However, this was not the case forstudies funded by industry, which favoured the experimentaldrug in 74% of trials.The material received during the study period mainlyincluded literature about a restricted and selected numberof newer drugs that were being heavily promoted duringthe study period. Articles addressing other importantquestions in oncology, including for example advances inthe multidisciplinary treatment of cancer, and otherimportant issues of interest were conspicuously under-represented in the collected material.In summary, we conclude that mailed educationalmaterial provided by pharmaceutical companies appears tobe biased to include selected positive data and trials on drugsof timely interest to the respective company. Althoughliterature services of pharmaceutical companies offer muchconvenience, physicians should not rely on unsolicitedliterature when reviewing the evidence of the clinical efficacyand safety of new drugs. Doctors should be aware of thepossible biases involved, review such material critically andconsider its implications for their continuous medicaleducation as well as their treatment decisions in clinicalpractice.C. Wick1,2, M. Egger1, S. Trelle1, P. Ju¨ni1 & M. F. Fey2*1Department of Social and Preventive Medicine and 2Department ofMedical Oncology, University of Bern, Inselspital, Bern, Switzerland(*E-mail: martin.fey@insel.ch)references1. Drug promotion: stealth, wealth, and safety. Lancet 1993; 341: 1507–1508.2. Rosenthal MB, Berndt ER, Donohue JM et al. Promotion of prescription drugs toconsumers. N Engl J Med 2002; 346: 498–505.3. Caudill TS, Lurie N, Rich EC. The influence of pharmaceutical industryadvertising on physician prescribing. J Drug Issues 1992; 22: 331–338.4. Cho MK, Bero LA. The quality of drug studies published in symposiumproceedings. Ann Intern Med 1996; 124: 485–489.5. Villanueva P, Peiro S, Librero J, Pereiro I. Accuracy of pharmaceuticaladvertisements in medical journals. Lancet 2003; 361: 27–32.6. Bowman MA. Pharmaceutical company/physician interactions. Finding thebalance. Arch Fam Med 1994; 3: 317–318.7. Bernardi D, Errante D, Bianco A, Salvagno L. Are sales representatives and thesale strategies of pharmaceutical companies getting too aggressive towardsphysicians? Ann Oncol 2007; 18: 607.8. Angell M. Excess in the pharmaceutical industry. CMAJ 2004; 171: 1451–1453.9. Avorn J, Chen M, Hartley R. Scientific versus commercial sources of influence onthe prescribing behavior of physicians. Am J Med 1982; 73: 4–8.10. Henry D, Doran E, Kerridge I et al. Ties that bind: multiple relationships betweenclinical researchers and the pharmaceutical industry. Arch Intern Med 2005;165: 2493–2496.11. Somerset M, Weiss M, Fahey T. Dramaturgical study of meetings betweengeneral practitioners and representatives of pharmaceutical companies;Commentary: dramaturgical model gives valuable insight. BMJ 2001; 323:1481–1484.12. Egger M, Davey Smith G. Meta-analysis: bias in location and selection of studies.BMJ 1998; 316: 61–66.13. De Bellefeuille C, Morrison CA, Tannock IF. The fate of abstracts submitted toa cancer meeting: factors which influence presentation and subsequentpublication. Ann Oncol 1992; 3: 187–191.14. Egger M, Davey Smith G. Meta-analysis: potentials and promise. BMJ 1997;315: 1371–1374.15. Ju¨ni P, Altman DG, Egger M. Assessing the quality of controlled clinicaltrials. In Egger M, Smith DG, Altman DG (eds): Systematic Reviews inHealth Care: Meta-Analysis in Context. London: BMJ Books, 2001: pp87–108.16. Schulz KF, Chalmers I, Hayes RJ, Altman D. Empirical evidence of bias.Dimensions of methodological quality associated with estimates of treatmenteffects in controlled trials. JAMA 1995; 273: 408–412.17. Djulbegovic B, Lacevic M, Cantor A et al. The uncertainty principle andindustry-sponsored research. Lancet 2000; 356: 635–638.doi:10.1093/annonc/mdm402letters to the editor Annals of Oncology1582 | letters to the editor Volume 18 |No. 9 | September 2007

The characteristics of unsolicited clinical oncology literature provided by pharmaceutical industry

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