Conflict of Interest in the Debate over Calcium-Channel Antagonists

doi:10.1056/NEJM199801083380206

Volume 338:101-106		January 8, 1998		Number 2

Conflict of Interest in the Debate over Calcium-Channel Antagonists

Henry Thomas Stelfox, M.D., Grace Chua, M.D., Keith O'Rourke, M.B.A., and Allan S. Detsky, M.D., Ph.D.

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ABSTRACT

Background Physicians' financial relationships with the pharmaceuticalindustry are controversial because such relationships may posea conflict of interest. It is unknown to what extent industrysupport of medical education and research influences the opinionsand behavior of clinicians and researchers. The recent debateover the safety of calcium-channel antagonists provided an opportunityto examine the effect of financial conflicts of interest.

Methods We searched the English-language medical literaturepublished from March 1995 through September 1996 for articlesexamining the controversy about the safety of calcium-channelantagonists. Articles were reviewed and classified as beingsupportive, neutral, or critical with respect to the use ofcalcium-channel antagonists. The authors of the articles wereasked about their financial relationships with both manufacturersof calcium-channel antagonists and manufacturers of competingproducts (i.e., beta-blockers, angiotensin-converting–enzymeinhibitors, diuretics, and nitrates). We examined the authors'published positions on the safety of calcium-channel antagonistsaccording to their financial relationships with pharmaceuticalcompanies.

Results Authors who supported the use of calcium-channel antagonistswere significantly more likely than neutral or critical authorsto have financial relationships with manufacturers of calcium-channelantagonists (96 percent, vs. 60 percent and 37 percent, respectively;P<0.001). Supportive authors were also more likely than neutralor critical authors to have financial relationships with anypharmaceutical manufacturer, irrespective of the product (100percent, vs. 67 percent and 43 percent, respectively; P <0.001).

Conclusions Our results demonstrate a strong association betweenauthors' published positions on the safety of calcium-channelantagonists and their financial relationships with pharmaceuticalmanufacturers. The medical profession needs to develop a moreeffective policy on conflict of interest. We support completedisclosure of relationships with pharmaceutical manufacturersfor clinicians and researchers who write articles examiningpharmaceutical products.

The safety of calcium-channel antagonists in the treatment ofcardiovascular disorders has recently become a controversialissue. A case–control study suggested a possible associationbetween the use of calcium-channel antagonists to treat hypertensionand an increased risk of myocardial infarction.¹ A meta-analysisof randomized, controlled trials in patients with ischemic heartdisease and a case–control study of antihypertensive medicationsin the elderly raised further questions about the safety ofcalcium-channel antagonists.²^,³ An intense debate followed inboth the medical literature and the lay press.

A Canadian television documentary, The Fifth Estate, reportedon Health Canada's review of calcium-channel antagonists andsuggested that the public was not being adequately protectedfrom potentially dangerous medications. The allegation thatan academic advisor to the Health Protection Branch of Healthand Welfare Canada (the body that reviews the safety of allpharmaceutical products) had financial relationships with manufacturersof calcium-channel antagonists raised an important questionabout physicians' objectivity in assessing the safety of drugs.

Physicians' interactions with pharmaceutical manufacturers arecontroversial. The pharmaceutical industry provides substantialfinancial support for both medical education and research. Whatis unknown is the extent to which support by the drug industryinfluences physicians' opinions and behavior. Limited scientificevidence suggests that physicians may be influenced by pharmaceuticalpromotions.⁴^,⁵^,⁶^,⁷ For example, a study by Chren and Landefelddemonstrated that physicians' requests to add particular drugsto hospital formularies were associated with interactions betweenphysicians and manufacturers.⁴

The debate about the safety of calcium-channel antagonists providedan opportunity to study financial conflicts of interest in medicine.Our project was designed to examine the relation between authors'published positions on the safety of calcium-channel antagonistsand their financial interactions with the pharmaceutical industry.

Methods

Study Questions

The primary question we addressed was whether there was an associationbetween authors' published positions on the safety of calcium-channelantagonists and their financial relationships with the pharmaceuticalindustry. Authors were surveyed about their financial relationshipswith pharmaceutical manufacturers, and this information wascompared with their published positions. We asked three specificquestions: Were authors who supported the use of calcium-channelantagonists more likely than other authors to have financialrelationships with manufacturers of calcium-channel antagonists?Were authors who criticized the use of calcium-channel antagonistsmore likely than other authors to have financial relationshipswith manufacturers of competing products (i.e., beta-blockers,angiotensin-converting–enzyme inhibitors, diuretics, andnitrates)? Were authors who supported the use of calcium-channelantagonists more likely than other authors to have financialrelationships with any pharmaceutical manufacturer?

Selection and Review of Articles

Authors were identified by reviewing articles on calcium-channelantagonists published between March 10, 1995, and September30, 1996. Pertinent articles (reports of original research,reviews, and letters to the editor) were identified with theuse of the Medline data base and reference lists from publishedarticles. Seventy-seven articles were initially selected.¹^,²^,³^,⁸^,⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁷¹^,⁷²^,⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷^,⁷⁸^,⁷⁹^,⁸⁰^,⁸¹Seven articles were excluded because they were primarily newsrelated, the authors could not be identified, or the authorswere officially writing on behalf of the pharmaceutical industry.⁸^,⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴Seventy articles were included in the study.¹^,²^,³^,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁷¹^,⁷²^,⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷^,⁷⁸^,⁷⁹^,⁸⁰^,⁸¹

The articles were reviewed with the use of a predefined classificationsystem (Table 1). Each article was classified as being supportive,neutral, or critical with respect to the use of calcium-channelantagonists. The articles were independently assessed by twoof us without knowledge of the authors' survey responses. Discrepancieswere discussed, and a third author was consulted if an agreementwas not reached. Authors were identified and assigned a classification(supportive, neutral, or critical) according to the classificationof their articles. Thirty authors had more than one article,but each author was assigned a single classification. Authorsclassified as neutral on the basis of one article but criticalor supportive on the basis of another were classified as criticalor supportive.

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Table 1. Classification of Authors' Positions on the Safety of Calcium-Channel Antagonists.

Survey Instrument

A survey instrument based on Chren and Landefeld's ⁴ questionnairewas developed to examine the authors' financial interactionswith pharmaceutical companies. The manufacturers of drugs usedto manage angina and hypertension were identified. Forty companieswere identified in Canada and the United States: 28 manufacturedonly products that compete with calcium-channel antagonists(beta-blockers, angiotensin-converting–enzyme inhibitors,diuretics, or nitrates), and 12 manufactured calcium-channelantagonists; 9 of the 12 also manufactured at least one competingproduct. The pharmaceutical manufacturers were listed alphabetically;the nature of their products was not revealed. For each of the40 manufacturers, authors were asked whether they had receivedany of five types of funding in the past five years: supportto attend a symposium (i.e., funds for travel expenses), anhonorarium to speak at a symposium, support to organize an educationalprogram, support to perform research, and employment or consultation.The questionnaire and the list of manufacturers are availablefrom the National Auxiliary Publications Service (^*).

The addresses of the corresponding authors were obtained fromthe articles, and the addresses of coauthors were requestedfrom the corresponding authors. All authors were mailed thesurvey questionnaire with a cover letter explaining the purposeof the study. Reminder letters and questionnaires were mailedto authors who did not respond to the first mailing within eightweeks.

Statistical Analysis

The strategy for the primary analysis was to answer each ofthe three specific study questions by determining associationsbetween the authors' positions on the safety of calcium-channelantagonists and their reported financial relationships withpharmaceutical manufacturers. The authors' survey responseswere coded according to the presence or absence of at leastone relationship with a manufacturer of a calcium-channel antagonist,a manufacturer of a competing product, or any pharmaceuticalmanufacturer. Logistic regression was performed individuallyfor each group of manufacturers, with the classification ofthe authors (supportive, neutral, or critical) treated as bothstrictly linear (coded as 2, 1, or 0) and nominal (unordered).⁸²^,⁸³^,⁸⁴The results are reported only as linear chi-square values andP values, since the results of the nominal analyses were similar.For the authors who reported financial relationships with pharmaceuticalmanufacturers, the number of relationships was assessed by linearregression.

The rate of response to the survey was analyzed according tothe classification of the authors with the use of logistic regression(linear and nominal). Agreement on the classification of theauthors was assessed with Spearman's rank-correlation test.Data were analyzed with S-PLUS software.⁸⁵

Results

Classification of Authors

Seventy articles (5 reports of original research, 32 reviewarticles, and 33 letters to the editor) were included in thestudy; 30 were classified as supportive,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰^,⁶¹17 as neutral,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰^,³¹and 23 as critical.¹^,²^,³^,⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁷¹^,⁷²^,⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷^,⁷⁸^,⁷⁹^,⁸⁰^,⁸¹Agreement on the classification of the articles by the two reviewerswas initially 81 percent (agreement on 57 of the 70 articles)and increased to 96 percent (67 of 70) after the reviewers haddiscussed the discrepancies. A third reviewer was required toresolve the disagreement on the classification of three articles.Interobserver variation was small for the initial reviewer agreementon article classification (Spearman's rank-correlation coefficient,0.82). Eighty-nine authors of the 70 articles were identifiedand assigned a classification according to that of their articles;36 authors were classified as supportive, 19 as neutral, and34 as critical.

Response Rates

Addresses were available for 86 of the 89 authors, and all 86were mailed questionnaires. Three coauthors (one supportive,one neutral, and one critical) were not mailed surveys becausetheir addresses were not provided by the corresponding authors.Of the 86 authors who were mailed surveys, 71 (83 percent) responded.Two authors (one supportive and one critical) refused to participatein the study. A total of 69 authors (80 percent) completed thesurvey. Table 2 shows the response rate according to the classificationof the authors. Sixty-nine percent of the authors who were supportiveof calcium-channel antagonists completed the survey, as comparedwith 83 percent of the neutral authors and 91 percent of thecritical authors (P = 0.02).

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Table 2. Rates of Response to the Survey.

Study Questions

The first question we addressed was whether supporters of calcium-channelantagonists were more likely than other authors to have financialrelationships with manufacturers of calcium-channel antagonists.The answer was yes. Ninety-six percent of the supportive authorshad financial relationships with manufacturers of calcium-channelantagonists, as compared with 60 percent of the neutral authorsand 37 percent of the critical authors (P<0.001) (Table 3).

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Table 3. Authors with Financial Relationships with Pharmaceutical Manufacturers.

Our second question was whether critics of calcium-channel antagonistswere more likely than other authors to have financial relationshipswith manufacturers of competing products (beta-blockers, angiotensin-converting–enzymeinhibitors, diuretics, and nitrates). The answer was no. Infact, supportive and neutral authors were more likely than criticalauthors to have financial interactions with manufacturers ofcompeting products (88 percent and 53 percent, respectively,vs. 37 percent; P<0.001).

Our third question was whether supporters of calcium-channelantagonists were more likely than other authors to have financialrelationships with any pharmaceutical manufacturer. The answerwas yes. One hundred percent of the supportive authors, as comparedwith 67 percent of the neutral authors and 43 percent of thecritical authors, had financial interactions with at least onepharmaceutical manufacturer (P<0.001).

The associations between the authors' positions on the safetyof calcium-channel antagonists and the presence or absence offinancial relationships with pharmaceutical manufacturers wereconsistent in the five categories of funding (funds for travelexpenses, honorariums for speeches, support for educationalprograms, research grants, and employment or consultation) (Table 4).Sixty-seven percent of the supportive authors reported threeor more of the five types of interactions, as compared with40 percent of the neutral authors and 13 percent of the criticalauthors (P<0.001). In the group of authors who had at leastone relationship with any pharmaceutical manufacturer, therewere no significant associations between an author's positionon the safety of calcium-channel antagonists and the mean numberof relationships.

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Table 4. Authors' Financial Relationships with Pharmaceutical Manufacturers.

Discussion

Our study was designed to examine financial conflicts of interestin the debate over calcium-channel antagonists. The resultsdemonstrate a strong association between authors' opinions aboutthe safety of calcium-channel antagonists and their financialrelationships with pharmaceutical manufacturers. Supportiveauthors were much more likely than critical authors to havefinancial associations with manufacturers of calcium-channelantagonists, as well as with manufacturers of other products.Conversely, critical authors were much less likely to be financiallyassociated with manufacturers of competing products.

Limitations of the Study

The results of this study need to be interpreted within thecontext of its limitations. First, the survey instrument usedwas simple and perhaps imperfect. Author–manufacturerrelationships were assessed simply as being present or absent.No estimates of monetary value were assigned to the relationshipsto assist in quantification. We also realized later that theauthors' business interests in pharmaceutical companies (e.g.,equities) were not assessed. The most serious weakness of thesurvey instrument, however, was that it provided only self-reporteddata on financial relationships. Independent verification ofthese relationships would be very difficult. Self-reportingcould potentially have biased the study results since the authorswere more likely to underreport than overreport interactionswith manufacturers. Most of the critical authors (91 percent)completed the survey, and we believe it is unlikely that theyunderreported their financial relationships, as compared withthe other authors. The supportive authors had a lower responserate (69 percent), yet all the supportive authors who respondedto the survey reported a financial relationship with at leastone manufacturer. We therefore believe that self-reporting isunlikely to have significantly influenced our study findings.

Second, we were unable to determine the temporal relation betweenauthors' published opinions and their financial interactionswith pharmaceutical manufacturers. The authors may have formulatedtheir opinions after having financial interactions with drugmanufacturers. However, it is equally plausible that the pharmaceuticalcompanies sought relationships with clinicians and researcherswho had already expressed favorable opinions of their products.

Guidelines for Disclosing Conflicts of Interest

The medical profession has failed to develop and enforce strictguidelines for disclosing conflicts of interest. Furthermore,many conflicts of interest may go unrecognized. In our study,the majority of authors (63 percent) had a financial relationshipwith either a manufacturer of a calcium-channel antagonist ora manufacturer of a competing product. However, only 2 of the70 articles included in the study disclosed the authors' potentialconflicts of interest.⁴¹^,⁵³ Clearly, our current disclosurepolicies are inadequate.

We propose a disclosure mechanism in the form of a questionnairefor authors: a simple two- or three-page document, similar tothe one used in our study, listing pharmaceutical manufacturersand inquiring about specific financial relationships with them.A questionnaire posing simple, concrete questions facilitatesthe disclosure of conflicts of interest. With this approach,ambiguity and accidentally missed conflicts, as recently notedin the New England Journal of Medicine,⁸⁶ would be avoided.Editorial staff would be in possession of all information onpotential conflicts of interest and would be able to make anappropriate decision about disclosure for each article published.

We believe that the pharmaceutical industry has an importantand constructive role in academic medicine. Pharmaceutical manufacturersprovide important support for both medical education and research.We also believe that medical journals risk severely limitingthe pool of experts available to debate medical issues if theyrestrict the publication of articles by clinicians and researcherswith conflicts of interest. Physicians and researchers simplyneed to disclose their financial relationships with pharmaceuticalmanufacturers appropriately. Medical professionals should beable to evaluate the merit of individual articles in the lightof the authors' disclosure of conflicts of interest.

The extent to which the pharmaceutical industry influences clinicians'and researchers' opinions cannot be determined by the resultsof our study. We believe that the authors we surveyed expressedtheir own opinions and were not influenced by financial relationshipswith pharmaceutical manufacturers. However, it is our opinionthat scientific authors are naive about public perceptions concerningsuch relationships. We wonder how the public would interpretthe debate over calcium-channel antagonists if it knew thatmost of the authors participating in the debate had undisclosedfinancial ties with pharmaceutical manufacturers. The medicalprofession needs to develop a strong policy governing conflictof interest. Full disclosure of relationships between physiciansand pharmaceutical manufacturers is necessary to affirm theintegrity of the medical profession and maintain public confidence.

This study received no financial support from the pharmaceuticalindustry. Dr. Stelfox has no financial relationships with thepharmaceutical industry; he has attended numerous Departmentof Medicine educational rounds sponsored by pharmaceutical manufacturers.Dr. Chua has received funding for travel from both manufacturersof calcium-channel antagonists and manufacturers of competingproducts. Mr. O'Rourke has no financial relationships with themanufacturers of calcium-channel antagonists or the manufacturersof competing products; he has attended industry-sponsored functionswhen invited by clinicians. Dr. Detsky has received honorariumsfor speeches and consulting fees from manufacturers of calcium-channelantagonists and manufacturers of competing products; he hasreceived research grants from Rhone–Poulenc Rorer Pharmaceuticals,Searle, and SmithKline Beecham Pharmaceuticals.

We are indebted to Drs. D.A. Redelmeier and M. Desreux for theirhelp in revising the manuscript.

^* See NAPS document no. 05439 for 5 pages of supplementary material.Order from NAPS c/o Microfiche Publications, P.O. Box 3513,Grand Central Station, New York, NY 10163-3513.

Source Information

From the Departments of Medicine (H.T.S., G.C., A.S.D.), Health Administration (K.O., A.S.D.), and Public Health Sciences (K.O.), University of Toronto; the Department of Medicine, Mount Sinai Hospital (A.S.D.); and the Department of Medicine, Toronto Hospital (A.S.D.) — all in Toronto.

Address reprint requests to Dr. Detsky at Mount Sinai Hospital, Rm. 427, 600 University Ave., Toronto, ON M5G 1X5, Canada.

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Conflict of Interest in the Debate over Calcium-Channel Antagonists
Meltzer J. I., Opie L., Strandgaard S., Detsky A. S., Stelfox H. T.
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N Engl J Med 1998; 338:1696-1698, Jun 4, 1998. Correspondence

Conflicts of Interest and Libel Action
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Extract | Full Text | PDF
N Engl J Med 2002; 346:1919-1920, Jun 13, 2002. Correspondence

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