Discrepancy between Results and Abstract Conclusions
`in Industry- vs Nonindustry-funded Studies Comparing
`Topical Prostaglandins
`
`TARIQ ALASBALI, MICHAEL SMITH, NOA GEFFEN, GRAHAM E. TROPE, JOHN G. FLANAGAN,
`YAPING JIN, AND YVONNE M. BUYS
`
`● PURPOSE: To investigate the relationship between
`industry- vs nonindustry-funded publications compar-
`ing the efficacy of topical prostaglandin analogs by
`evaluating the correspondence between the statistical
`significance of the publication’s main outcome measure
`and its abstract conclusions.
`● DESIGN: Retrospective, observational cohort study.
`● METHODS: English publications comparing the ocular
`hypotensive efficacy between any or all of latanoprost,
`travoprost, and bimatoprost were searched from the
`MEDLINE database. Each article was reviewed by three
`independent observers and was evaluated for source of
`funding, study quality, statistically significant main out-
`come measure, correspondence between results of main
`outcome measure and abstract conclusion, number of
`intraocular pressure outcomes compared, and journal
`impact factor. Funding was determined by published
`disclosure or, in cases of no documented disclosure, the
`corresponding author was contacted directly to confirm
`industry funding. Discrepancies were resolved by con-
`sensus. The main outcome measure was correspondence
`between abstract conclusion and reported statistical sig-
`nificance of the publications’ main outcome measure.
`● RESULTS: Thirty-nine publications were included, of
`which 29 were industry funded and 10 were nonindustry
`funded. The published abstract conclusion was not con-
`sistent with the results of the main outcome measure in
`18 (62%) of 29 of the industry-funded studies compared
`with zero (0%) of 10 of the nonindustry-funded studies
`(P ⴝ .0006). Twenty-six (90%) of the industry-funded
`studies had proindustry abstract conclusions.
`● CONCLUSIONS: Twenty-four percent of the industry-
`funded publications had a statistically significant main
`outcome measure; however, 90% of the industry-funded
`
`See accompanying Editorial on page 1.
`Accepted for publication Jul 1, 2008.
`From the Department of Ophthalmology and Vision Sciences, Uni-
`versity of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
`(T.A., M.S., N.G., G.E.T., J.G.F., Y.M.B.); the Department of Ophthal-
`mology, King Faisal University, King Fahad Hospital of the University,
`Riyad, Saudi Arabia (T.A.); the School of Optometry, University of
`Waterloo, Waterloo, Ontario, Canada (J.G.F.); and the Department
`of Public Health Sciences, University of Toronto, Toronto, Ontario,
`Canada (Y.J.).
`Inquiries to Yvonne M. Buys, Toronto Western Hospital, 399 Bathurst
`Street, EW6-405, Toronto, Ontario, Canada M5T 2S8; e-mail: y.buys@
`utoronto.ca
`
`0002-9394/09/$36.00
`doi:10.1016/j.ajo.2008.07.005
`
`© 2009 BY ELSEVIER INC. ALL RIGHTS RESERVED.
`
`studies had proindustry abstract conclusions. Both read-
`ers and reviewers should scrutinize publications carefully
`to ensure that data support the authors’ conclusions.
`(Am J Ophthalmol 2009;147:33–38. © 2009 by
`Elsevier Inc. All rights reserved.)
`
`F INANCIAL RELATIONSHIPS BETWEEN PHARMACEUTI-
`
`cal companies and researchers and funding of med-
`ical
`research by drug companies has
`increased
`dramatically during the last two decades.1– 4 This can result
`in industry bias where the source of funding of clinical
`trials either affects the results in a systematic way or leads
`to selective presentation of the results. Industry funding
`often has been associated with proindustry results2,5–20 and
`publication bias,21–23 which can affect the interpretation
`and presentation of outcomes resulting in conclusions that
`overstate results without statistical support. The purpose
`of this study was to investigate the relationship between
`industry- vs nonindustry-funded publications comparing
`ocular hypotensive efficacy of the topical prostaglandin
`analogs (PGA) latanoprost 0.005%, travoprost 0.004%,
`and bimatoprost 0.03% by evaluating the correspondence
`between the statistical significance of the publication’s main
`outcome measure and its published abstract conclusions.
`
`METHODS
`
`A MEDLINE SEARCH FROM 1966 TO THE SECOND WEEK OF
`November 2007 using any combination of the keywords
`latanoprost, travoprost, and bimatoprost was conducted. The
`title and abstracts from the initial search were reviewed
`and those included were English language publications
`comparing the intraocular pressure (IOP)-lowering efficacy
`of any combination of latanoprost; travoprost; or bimato-
`prost. The complete articles were obtained and the refer-
`ences also were searched to identify relevant publications
`missed during the initial search.
`Each publication was reviewed by three independent
`observers using a standardized data collection sheet eval-
`uating: source of funding, industry author, study quality,
`main outcome measure, statistical significance (P ⬍ .05) of
`main outcome measure, abstract conclusion, correspon-
`dence between statistical significance (P ⬍ .05) of main
`Exhibit 1047
`ARGENTUM
`IPR2017-01053
`
`33
`
`000001
`
`

`

`TABLE 1. Grading of Study Quality
`
`Level
`
`Criteria
`
`1A: Meta-analysis (to assign this level,
`you must answer ‘yes’ to all questions)
`
`Does the paper report a comprehensive search for evidence?
`
`1A: Large RCT (to assign this level, you
`must answer ‘yes’ to all questions)
`
`1B: NRCT
`2: RCT
`3
`4
`
`Did the authors avoid bias in selecting articles for inclusion?
`Did the authors asses each article for validity?
`Does the paper report clear conclusions that are supported by the data and appropriate
`analysis?
`Were patients randomly allocated to treatment groups?
`
`Was follow-up at least 80% complete?
`Were both the patients and the investigators blind to the treatment the patient received?
`Were the patients analyzed in the treatment groups to which they were assigned?
`Was the sample size large enough to detect the outcome of interest?
`NRCT or cohort study with indisputable results
`RCT or overview that did not meet level 1
`NRCT or cohort study
`Other (case series without controls, case report, expert opinion, etc.)
`
`NRCT ⫽ nonrandomized controlled trial; RCT ⫽ randomized controlled trial.
`
`TABLE 2. Summary of Industry– vs Nonindustry-funded Studies Comparing Topical Prostaglandins
`
`Outcome Studied
`
`Industry-funded (n ⫽ 29)
`
`Nonindustry-funded (n ⫽ 10)
`
`Noncorrespondence of main outcome and conclusions
`Statistically significant (P ⬍ .05) main outcome
`Number of IOP comparisons, mean ⫾ SD (median, range)
`Mean study quality
`Industry coauthor
`Journal impact factor
`
`18 (62%)
`7 (24%)
`17.4 ⫾ 11.6 (14, 1 to 45)
`2.4 ⫾ 1.1
`18 (62%)
`2.14 ⫾ 1.32
`
`0 (0%)
`2 (20%)
`13.0 ⫾ 11.4 (8, 1 to 30)
`2.0 ⫾ 0.7
`N/A
`2.33 ⫾ 1.51
`
`P value
`
`.0006a
`1.00a
`.31b
`.27b
`
`.72b
`
`IOP ⫽ intraocular pressure; N/A ⫽ not applicable; SD ⫽ standard deviation.
`aFisher exact test.
`bStudent t test.
`
`outcome measure and abstract conclusion, total number of
`IOP outcomes compared, and journal impact factor. Any
`discrepancies between the three reviewers were resolved by
`consensus.
`Funding was determined by published disclosure, or in
`cases of no documented disclosure, the corresponding
`author was contacted directly to confirm any direct fund-
`ing of the study. In one case, the pharmaceutical company
`was contacted to verify funding. Study quality was assessed
`according to the criteria in Table 1.24 Journal impact
`factors from 2006 were assigned to each publication.
`The main outcome measure was the correspondence
`between the statistical significance of the publication’s
`main outcome measure and its published abstract con-
`clusion. Statistical analysis included the Fisher exact
`test for categorical data and the Student t test for
`continuous data.
`
`RESULTS
`
`A TOTAL OF 180 ARTICLES WERE IDENTIFIED BY THE ORIGI-
`nal search. After reviewing the abstracts, 39 met the
`inclusion criteria and were included in the study. In
`reviewing the references of these publications, no addi-
`tional publications were found. Of the 39 publications, 35
`were studies that directly compared two or three of the
`PGAs and four were meta-analyses. Thirty-five of the
`publications included a disclosure statement, and four had
`no documented disclosure. The authors were contacted
`regarding these four publications; two publications25,26
`confirmed industry funding of the study and two reported
`no funding. One of the publications for which the author
`denied industry funding subsequently was discovered to
`have received industry funding after direct communication
`with the pharmaceutical company and was allocated to
`
`34
`
`AMERICAN JOURNAL OF OPHTHALMOLOGY
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`

`industry funding. Twenty-nine (74%) of the publications
`were industry funded (18 by Allergan, Irvine, California,
`USA,25– 42 10 by Alcon, Fort Worth, Texas, USA43–52 and
`one by Pfizer, New York, New York, USA53) and 10 (26%)
`were nonindustry funded (nine had no funding54 – 62 and
`one had government funding63). There was an industry
`coauthor in 18 (62%) of the industry-funded publications.
`The results are summarized in Table 2.
`Statistically significant main outcome measures were
`reported in 7 (24%) industry-funded publications and in 2
`(20%) nonindustry-funded publications (P ⫽ 1.00, Fisher
`exact test). Correspondence between the results of the
`main outcome measure and the abstract conclusions was
`found in 11 (38%) of the industry-funded publications
`vs 10 (100%) of the nonindustry-funded publications
`(P ⫽ .0006, Fisher exact test). Twenty-six (90%) of the
`industry-funded studies had proindustry conclusions.
`The mean number of IOP comparisons reported were
`17.4 ⫾ 11.6 for industry-funded publications and 13.0 ⫾
`11.4 for nonindustry-funded publications (P ⫽ .31, Stu-
`dent t test). The mean study quality was 2.4 ⫾ 1.1 for
`industry-funded publications compared with 2.0 ⫾ 0.7 for
`nonindustry-funded publications (P ⫽ .27, Student t test).
`The mean journal impact factor also was similar between
`industry-funded (2.14) and nonindustry-funded (2.33)
`publications (P ⫽ .72, Student t test).
`
`DISCUSSION
`
`WE FOUND THAT 62% OF THE INDUSTRY-FUNDED VS NONE
`of the nonindustry-funded studies’ abstract conclusions did
`not correspond with the results of the main outcome
`measure (P ⫽ .0006, Fisher exact test). Although only
`24% of the industry-funded publications had a statistically
`significant main outcome measure, 90% of the industry
`funded studies had a proindustry abstract conclusion.
`The influence of industry on publications involving a
`wide range of diseases and drugs is well documented.2,5–20
`Kjaergard and Als-Nielsen reviewed 159 randomized con-
`trolled trials from 12 specialties and found that when
`financial interests were disclosed, the authors’ conclusions
`significantly favored experimental intervention.11 Lexchin
`and associates reviewed 30 pharmaceutical-sponsored stud-
`ies and found “systematic bias to the outcome of published
`research funded by the pharmaceutical industry.”13 Als-
`Nielsen and associates evaluated 370 randomized con-
`trolled trials over a broad area of diseases and found that
`conclusions significantly favored experimental drugs in
`trials funded by for-profit organizations.15 A review of 124
`meta-analyses of antihypertensives found that industry
`support was not associated with more favorable results, but
`was associated with more favorable conclusions.20 To our
`knowledge, ours is the first attempt to determine industry
`bias in ophthalmology publications.
`
`Prostaglandin analogs currently are the first-line therapy
`for the treatment of glaucoma, representing 43.9% of
`glaucoma medications dispensed in Ontario, Canada, in
`2007. Latanoprost 0.005% (Pfizer) was first available in
`Ontario in June 1997,
`followed by travoprost 0.004%
`(Alcon) in November 2001 and bimatoprost 0.03% (Al-
`lergan) in May 2002. These three medications belong to
`the same class and therefore are competing directly for the
`same market share. The use of PGAs is influenced by the
`number and quality of publications.
`Of the 39 publications studied, 29 (74%) were industry
`funded. The high proportion of industry-funded studies is
`consistent with reports of increased funding of biomedical
`research by the biomedical industry.1– 4 Our definition of
`industry funding, however, may be considered conservative
`because we did not investigate the financial ties of each
`author and included only studies with direct industry
`funding. Evaluating financial disclosures of individual au-
`thors is difficult because many authors have support from
`several companies, although the amount of support per
`company may vary.
`Similar to studies in other disciplines, we found no
`difference in significant main outcome measures,10,16,20,23
`study quality,2,7,10,11,13,15,16,23 or journal impact factor8,15
`between industry- and nonindustry-funded studies compar-
`ing PGAs. Four of the seven industry-funded studies with
`significant main outcome measure were of the lowest level
`of quality (level 4).29,35,37,40 There were no level four
`studies in the nonindustry-funded group. Six of the eight
`industry-funded publications with level four study quality
`were published in journals with a higher (⬎ 2.2) impact
`factor.29,35–37,40,52
`The discrepancy between the results of the main out-
`come measure and abstract conclusions stems from the
`interpretation of surrogate outcomes or multiple compari-
`sons assigning undue attention to significant results while
`minimizing nonsignificant results.21 This is commonly
`referred to as “spin.” To evaluate for possible data dredging,
`we compared the total number of IOP outcome compari-
`sons presented in the results and found no difference
`between industry- and nonindustry-funded studies. The
`mean number of IOP outcome measures was 17.4 ⫾ 11.6
`(range, one to 45) for industry-funded publications and
`13.0 ⫾ 11.4 (range, one to 30) for nonindustry-funded
`publications (P ⫽ .31).
`This study raises concerns regarding undue industry
`influence in publications on PGAs. Less industry funding
`and increased funding by peer-reviewed governmental
`agencies or other organizations may remove this bias.
`Authors should provide transparency in the interpretation
`and conclusions of their study, and it is the role of journal
`editors and reviewers to ensure that data are not misrep-
`resented. It is important that journals develop strong
`guidelines to limit potential bias by creating minimum
`standards in reporting disclosure and results. Full disclo-
`sure of both authors and reviewers and funding source of
`
`VOL. 147, NO. 1
`
`INDUSTRY BIAS IN PROSTAGLANDIN STUDIES
`
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`
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`

`the study is necessary. Three of the studies in our review
`were funded directly by industry; however, there was no
`published disclosure. The requirement of registration of
`all clinical trials at the time of design and before the
`collection of data and making available all data could
`minimize inappropriate data analysis and selective re-
`porting of results. The inclusion in the abstract of a
`
`heading specifying the main outcome measure and the
`statistical results of the main outcome measure may
`improve transparency of the study findings. Ultimately,
`however, it is the responsibility of the reader to scruti-
`nize abstract conclusions carefully to ensure that they
`are supported by the data reported in the RESULTS
`SECTION of the article.
`
`THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. DR BUYS IS AN ADVISORY BOARD
`member for Allergan Inc and Pfizer and received lecture fees from Alcon. Drs Buys and Trope receive grants from Allergan Inc, Pfizer, and Canadian
`Institutes of Health Research. Dr Smith received a travel grant from Alcon and Allergan Inc. Involved in design of study (Y.M.B.); literature search
`(Y.M.B., T.A.); reviewing publications (T.A., M.S., N.G., G.E.T., J.G.F., Y.M.B.); statistical analysis (Y.M.B., Y.J.); and preparation of manuscript
`(Y.M.B., T.A.). This study was a review of published literature and Institutional Review Board approval was not necessary.
`
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`Dr Yvonne Buys completed her MD, ophthalmology residency, and glaucoma fellowship at the University of Toronto,
`Toronto, Canada. She is currently an Associate Professor at the University of Toronto, Department of Ophthalmology,
`Co-Director of the Glaucoma Unit at the University Health Network, and President of the Canadian Glaucoma Society.
`Dr Buys is involved in training ophthalmology residents and glaucoma fellows. She has published over 60 peer-reviewed
`papers and three book chapters in the area of glaucoma.
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`Dr Tariq Alasbali completed his MD, ophthalmology residency at King Faisal University and a glaucoma fellowship at
`King Khaled Eye Specialist Hospital (KKESH) in Saudi Arabia. Dr Alasbali completed a research fellowship and currently
`he is a clinical glaucoma fellow at the University of Toronto, Department of Ophthalmology. Dr Alasbali received a
`Canadian Ophthalmological Society award for excellence in ophthalmic research in 2007.
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