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How I Choose a Prostaglandin Analogue
EDITORIALS How I Choose a Prostaglandin Analogue WALLACE L. M. ALWARD
W
HEN I BEGAN MY OPHTHALMOLOGY RESIDENCY,
beta-adrenergic antagonists and laser trabeculoplasty had recently been introduced. Therefore, the introduction of prostaglandin analogues (PGAs) in 1996 has been the most important glaucoma therapeutic advance of my career. The original PGA, latanoprost (Xalatan; Pfizer Inc, New York, New York, USA) quickly became the most prescribed glaucoma medication because of its outstanding efficacy, safety, tolerability, and daily dosing schedule. The 2007 sales of latanoprost-based medications alone were $1.6 billion (http://www.pfizer.com). The highly profitable prostaglandin analogue market has led to fierce competition, dubbed the “prostaglandin wars,”1 and has generated intense pressure on ophthalmologists and health plans to choose one manufacturer’s PGA over the others. How does one choose between these agents? I have always admonished my residents and fellows to eschew biased information from pharmaceutical representatives and to instead rely on the peer-reviewed literature. I am now not sure that this is sage advice. In this issue of THE JOURNAL, Alasbali and associates provide data to support what has been long suspected: that corporate-sponsored studies overwhelmingly show the superiority of the sponsor’s own product.2 In 90% of corporate-sponsored papers, the abstract conclusion favored the sponsor’s agent.2 I had long wondered how manufacturers could so reliably generate papers that support their own drugs. Are they brilliant study designers? Are there piles of studies showing the inferiority of their products filling warehouses? One part of the answer is simpler, much slicker, and borrowed from politics: spin! Regardless of the outcome of the study, make the abstract conclusion say that the sponsor’s product is in some way superior. While 90% of corporate-sponsored papers had abstract conclusions favoring the sponsor’s product, the data presented in the body of the text showed a significant outcome measure only 24% of the time.2 And, while the abstract conclusion corresponded to the main outcome measure in 100% of non–industryfunded studies, this correspondence was found in only 38% of See accompanying Article on page 33. Accepted for publication Aug 4, 2008. From the Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa. Inquiries to Wallace L. M. Alward, Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa 52242; e-mail: [email protected] 0002-9394/09/$36.00 doi:10.1016/j.ajo.2008.08.004
©
2009 BY
industry-funded studies. Similar results have been reported in the major general medicine journals in which the abstracts were inaccurate 18% to 68% of the time3 and often failed to include important information about harm.4 Spinning the abstract is brilliant. The published literature has expanded dramatically and few people have the time to thoroughly read all papers in all relevant journals. Studies have documented that physicians often read only the abstract of an article and may not have the time or interest to study the entire paper. For example, a study of internists found that they relied on only the abstracts of 63% of papers that they “read.”5 Here are two examples of how this works. One comparison paper concluded: “At the end of this 30-day trial, once-daily bimatoprost 0.03% provided better diurnal intraocular pressure (IOP) control than latanoprost and was safe and well tolerated in patients with ocular hypertension and glaucoma.”6 Upon reading the manuscript, one finds no significant difference in mean IOP at day 14 or day 29 —interestingly, these were the primary outcome measures but were not mentioned in the abstract conclusion. There was also no difference in achieving a target IOP of ⱕ15 mm Hg and no difference in mean IOP averaged over the diurnal curve or at any point during the diurnal curve. A significant difference (P ⫽ .04) was noted only when comparing the area under the entire diurnal curve at day 29. However, there is no evidence that this P value was corrected for multiple measures. We traditionally consider a P value of ⬍.05 as being “statistically significant.” This means that there is a 95% likelihood that an observed correlation is not falsely positive, in other words not occurring simply by chance. However, because the authors studied at least eight outcomes, there was only a (0.95)8, or 66%, likelihood that there would not be a chance “significant” finding—and a 34% chance that there would.7 In order to correct for this the P value should, in essence, be multiplied by the number of different looks the authors had at the data. This is known as the Bonferroni correction and means that the P value of .04 should be multiplied by eight.8 This would yield a hardly compelling P value of .32. In another article, the abstract of a meta-analysis comparing travoprost and bimatoprost to latanoprost concluded that: “Travoprost and bimatoprost may have greater efficacy in lowering IOP for patients with ocular hypertension (OHT) or glaucoma.”9 While there were a total of 1,318 patients from nine studies included in this analysis, there was no hint of a
ELSEVIER INC. ALL
RIGHTS RESERVED.
1
significant difference between bimatoprost and latanoprost (P ⫽ .24) or between travoprost and latanoprost (P ⫽ .53). The data were then adjusted for IOP at inclusion and for the length of follow-up. There was still no significant difference. A significant difference of P ⫽ .03 could only be achieved by lumping bimatoprost and travoprost together for the rather tenuous reason that they share a “higher affinity for the FP receptor.” As in the previously mentioned study, there was no correction for these multiple looks at the data. The manufacturer of travoprost sponsored the study, the abstract of which would have us believe that it is equivalent to bimatoprost and superior to latanoprost, neither of which was proven. As a reviewer, I have probably not scrutinized the abstract as critically as the body of the text, or even the references. The reviewers may be concentrating on the body of the text while the readers are often concentrating on the abstract. The relationships between physicians and the pharmaceutical industry have come under increasing scrutiny in the popular press and in the medical literature. Recent books detail the profound influence that the pharmaceutical industry exerts on American physicians.10,11 Litigation against Merck & Co permitted unprecedented access to the processes behind the publication of papers supporting pharmaceuticals—specifically rofecoxib (Vioxx; Merck & Co Inc, Whitehouse Station, New Jersey, USA). A review of those studies documented widespread guest authorship and ghostwriting.12 Guest authorship occurs when a company or a hired medical publishing company writes a paper and then gives the authorship to a prominent member of the medical community— often someone who had nothing to
do with the study. Merck’s guest authors frequently received honoraria as well as academic credit and, in half of review articles, failed to disclose any financial relationship with the company.12 Ghostwriters are company employees or hired medical writers who are not listed as contributors. This timely article by Alasbali and associates should serve as a wake-up call for ophthalmology. When involved in pharmaceutical studies, we must insist on the right to publish the data accurately, without allowing the sponsor to spin the abstract conclusions. We must resist offers to serve as guest authors. Editors, editorial boards, and reviewers must be vigilant to keep the abstracts true to the body of the text and to eliminate any pro-sponsor distortions from finding their way into the literature. I believe that journals should have all corporate-sponsored manuscripts evaluated by biostatisticians to prevent inappropriate statistical manipulation.13,14 So, what do I do, and what do I teach to my residents and fellows? I read the peer-reviewed literature but now recognize that, while the body of the manuscript should be fact, the abstract conclusion may be fiction. I use all of the PGAs to develop my own opinion on how well they work and how well they are tolerated. I talk to trusted colleagues about their experience. It is sad that we each need to go through this process and we are not able to confidently rely on the peer-reviewed literature to guide us. However, I am hopeful that the paper by Alasbali and associates will positively impact the way that we write and review corporate-sponsored manuscripts and lead to a more reliable body of literature.
THE AUTHOR INDICATES NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. THE AUTHOR WAS INVOLVED IN design and conduct of study; data collection; analysis and interpretation of data; and preparation, review, and approval of the manuscript.
8. Bland JM, Altman DG. Multiple significance tests: the Bonferroni method. BMJ 1995;310:170. 9. Denis P, Lafuma A, Khoshnood B, Mimaud V, Berdeaux G. A meta-analysis of topical prostaglandin analogues intraocular pressure lowering in glaucoma therapy. Curr Med Res Opin 2007;23:601– 608. 10. Angell M. The truth about the drug companies: How they deceive us and what to do about it. New York, New York: Random House Trade Paperbacks, 2005. 11. Kassirer JP. On the take: how America’s complicity with big business can endanger your health. New York, New York: Oxford University Press, 2005. 12. Ross JS, Hill KP, Egilman DS, Krumholz HM. Guest authorship and ghostwriting in publications related to rofecoxib: a case study of industry documents from rofecoxib litigation. JAMA 2008;299:1800 –1812. 13. Alward WL. Additive efficacy of unoprostone isopropyl 0.12% (Rescula) to latanoprost 0.005%. Am J Ophthalmol 2001;132:449 – 451. 14. Eisenberg DL. Additive efficacy of unoprostone isopropyl 0.12% (Rescula) to latanoprost 0.005%. Am J Ophthalmol 2001;132:448 – 449.
REFERENCES 1. Kaufman PL. The prostaglandin wars. Am J Ophthalmol 2003;136:727–728. 2. Alasbali T, Smith M, Geffen N. Discrepancy between results and abstract conclusions in industry vs nonindustry-funded studies comparing topical prostaglandins. Am J Ophthalmol 2009;147:33–38. 3. Pitkin RM, Branagan MA, Burmeister LF. Accuracy of data in abstracts of published research articles. JAMA 1999;281: 1110 –1111. 4. Bernal-Delgado E, Fisher ES. Abstracts in high profile journals often fail to report harm. BMC Med Res Methodol 2008;8:14. 5. Saint S, Christakis D, Saha S, et al. Journal reading habits of internists. J Gen Intern Med 2000;15:881– 884. 6. DuBiner H, Cooke D, Dirks M, Stewart WC, VanDenburgh AM, Felix C. Efficacy and safety of bimatoprost in patients with elevated intraocular pressure: a 30-day comparison with latanoprost. Surv Ophthalmol 2001;45:S353–360. 7. Tukey JW. Some thoughts on clinical trials, especially problems of multiplicity. Science 1977;198:679 – 684.
2
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
JANUARY 2009
W
HEN I BEGAN MY OPHTHALMOLOGY RESIDENCY,
beta-adrenergic antagonists and laser trabeculoplasty had recently been introduced. Therefore, the introduction of prostaglandin analogues (PGAs) in 1996 has been the most important glaucoma therapeutic advance of my career. The original PGA, latanoprost (Xalatan; Pfizer Inc, New York, New York, USA) quickly became the most prescribed glaucoma medication because of its outstanding efficacy, safety, tolerability, and daily dosing schedule. The 2007 sales of latanoprost-based medications alone were $1.6 billion (http://www.pfizer.com). The highly profitable prostaglandin analogue market has led to fierce competition, dubbed the “prostaglandin wars,”1 and has generated intense pressure on ophthalmologists and health plans to choose one manufacturer’s PGA over the others. How does one choose between these agents? I have always admonished my residents and fellows to eschew biased information from pharmaceutical representatives and to instead rely on the peer-reviewed literature. I am now not sure that this is sage advice. In this issue of THE JOURNAL, Alasbali and associates provide data to support what has been long suspected: that corporate-sponsored studies overwhelmingly show the superiority of the sponsor’s own product.2 In 90% of corporate-sponsored papers, the abstract conclusion favored the sponsor’s agent.2 I had long wondered how manufacturers could so reliably generate papers that support their own drugs. Are they brilliant study designers? Are there piles of studies showing the inferiority of their products filling warehouses? One part of the answer is simpler, much slicker, and borrowed from politics: spin! Regardless of the outcome of the study, make the abstract conclusion say that the sponsor’s product is in some way superior. While 90% of corporate-sponsored papers had abstract conclusions favoring the sponsor’s product, the data presented in the body of the text showed a significant outcome measure only 24% of the time.2 And, while the abstract conclusion corresponded to the main outcome measure in 100% of non–industryfunded studies, this correspondence was found in only 38% of See accompanying Article on page 33. Accepted for publication Aug 4, 2008. From the Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa. Inquiries to Wallace L. M. Alward, Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa 52242; e-mail: [email protected] 0002-9394/09/$36.00 doi:10.1016/j.ajo.2008.08.004
©
2009 BY
industry-funded studies. Similar results have been reported in the major general medicine journals in which the abstracts were inaccurate 18% to 68% of the time3 and often failed to include important information about harm.4 Spinning the abstract is brilliant. The published literature has expanded dramatically and few people have the time to thoroughly read all papers in all relevant journals. Studies have documented that physicians often read only the abstract of an article and may not have the time or interest to study the entire paper. For example, a study of internists found that they relied on only the abstracts of 63% of papers that they “read.”5 Here are two examples of how this works. One comparison paper concluded: “At the end of this 30-day trial, once-daily bimatoprost 0.03% provided better diurnal intraocular pressure (IOP) control than latanoprost and was safe and well tolerated in patients with ocular hypertension and glaucoma.”6 Upon reading the manuscript, one finds no significant difference in mean IOP at day 14 or day 29 —interestingly, these were the primary outcome measures but were not mentioned in the abstract conclusion. There was also no difference in achieving a target IOP of ⱕ15 mm Hg and no difference in mean IOP averaged over the diurnal curve or at any point during the diurnal curve. A significant difference (P ⫽ .04) was noted only when comparing the area under the entire diurnal curve at day 29. However, there is no evidence that this P value was corrected for multiple measures. We traditionally consider a P value of ⬍.05 as being “statistically significant.” This means that there is a 95% likelihood that an observed correlation is not falsely positive, in other words not occurring simply by chance. However, because the authors studied at least eight outcomes, there was only a (0.95)8, or 66%, likelihood that there would not be a chance “significant” finding—and a 34% chance that there would.7 In order to correct for this the P value should, in essence, be multiplied by the number of different looks the authors had at the data. This is known as the Bonferroni correction and means that the P value of .04 should be multiplied by eight.8 This would yield a hardly compelling P value of .32. In another article, the abstract of a meta-analysis comparing travoprost and bimatoprost to latanoprost concluded that: “Travoprost and bimatoprost may have greater efficacy in lowering IOP for patients with ocular hypertension (OHT) or glaucoma.”9 While there were a total of 1,318 patients from nine studies included in this analysis, there was no hint of a
ELSEVIER INC. ALL
RIGHTS RESERVED.
1
significant difference between bimatoprost and latanoprost (P ⫽ .24) or between travoprost and latanoprost (P ⫽ .53). The data were then adjusted for IOP at inclusion and for the length of follow-up. There was still no significant difference. A significant difference of P ⫽ .03 could only be achieved by lumping bimatoprost and travoprost together for the rather tenuous reason that they share a “higher affinity for the FP receptor.” As in the previously mentioned study, there was no correction for these multiple looks at the data. The manufacturer of travoprost sponsored the study, the abstract of which would have us believe that it is equivalent to bimatoprost and superior to latanoprost, neither of which was proven. As a reviewer, I have probably not scrutinized the abstract as critically as the body of the text, or even the references. The reviewers may be concentrating on the body of the text while the readers are often concentrating on the abstract. The relationships between physicians and the pharmaceutical industry have come under increasing scrutiny in the popular press and in the medical literature. Recent books detail the profound influence that the pharmaceutical industry exerts on American physicians.10,11 Litigation against Merck & Co permitted unprecedented access to the processes behind the publication of papers supporting pharmaceuticals—specifically rofecoxib (Vioxx; Merck & Co Inc, Whitehouse Station, New Jersey, USA). A review of those studies documented widespread guest authorship and ghostwriting.12 Guest authorship occurs when a company or a hired medical publishing company writes a paper and then gives the authorship to a prominent member of the medical community— often someone who had nothing to
do with the study. Merck’s guest authors frequently received honoraria as well as academic credit and, in half of review articles, failed to disclose any financial relationship with the company.12 Ghostwriters are company employees or hired medical writers who are not listed as contributors. This timely article by Alasbali and associates should serve as a wake-up call for ophthalmology. When involved in pharmaceutical studies, we must insist on the right to publish the data accurately, without allowing the sponsor to spin the abstract conclusions. We must resist offers to serve as guest authors. Editors, editorial boards, and reviewers must be vigilant to keep the abstracts true to the body of the text and to eliminate any pro-sponsor distortions from finding their way into the literature. I believe that journals should have all corporate-sponsored manuscripts evaluated by biostatisticians to prevent inappropriate statistical manipulation.13,14 So, what do I do, and what do I teach to my residents and fellows? I read the peer-reviewed literature but now recognize that, while the body of the manuscript should be fact, the abstract conclusion may be fiction. I use all of the PGAs to develop my own opinion on how well they work and how well they are tolerated. I talk to trusted colleagues about their experience. It is sad that we each need to go through this process and we are not able to confidently rely on the peer-reviewed literature to guide us. However, I am hopeful that the paper by Alasbali and associates will positively impact the way that we write and review corporate-sponsored manuscripts and lead to a more reliable body of literature.
THE AUTHOR INDICATES NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. THE AUTHOR WAS INVOLVED IN design and conduct of study; data collection; analysis and interpretation of data; and preparation, review, and approval of the manuscript.
8. Bland JM, Altman DG. Multiple significance tests: the Bonferroni method. BMJ 1995;310:170. 9. Denis P, Lafuma A, Khoshnood B, Mimaud V, Berdeaux G. A meta-analysis of topical prostaglandin analogues intraocular pressure lowering in glaucoma therapy. Curr Med Res Opin 2007;23:601– 608. 10. Angell M. The truth about the drug companies: How they deceive us and what to do about it. New York, New York: Random House Trade Paperbacks, 2005. 11. Kassirer JP. On the take: how America’s complicity with big business can endanger your health. New York, New York: Oxford University Press, 2005. 12. Ross JS, Hill KP, Egilman DS, Krumholz HM. Guest authorship and ghostwriting in publications related to rofecoxib: a case study of industry documents from rofecoxib litigation. JAMA 2008;299:1800 –1812. 13. Alward WL. Additive efficacy of unoprostone isopropyl 0.12% (Rescula) to latanoprost 0.005%. Am J Ophthalmol 2001;132:449 – 451. 14. Eisenberg DL. Additive efficacy of unoprostone isopropyl 0.12% (Rescula) to latanoprost 0.005%. Am J Ophthalmol 2001;132:448 – 449.
REFERENCES 1. Kaufman PL. The prostaglandin wars. Am J Ophthalmol 2003;136:727–728. 2. Alasbali T, Smith M, Geffen N. Discrepancy between results and abstract conclusions in industry vs nonindustry-funded studies comparing topical prostaglandins. Am J Ophthalmol 2009;147:33–38. 3. Pitkin RM, Branagan MA, Burmeister LF. Accuracy of data in abstracts of published research articles. JAMA 1999;281: 1110 –1111. 4. Bernal-Delgado E, Fisher ES. Abstracts in high profile journals often fail to report harm. BMC Med Res Methodol 2008;8:14. 5. Saint S, Christakis D, Saha S, et al. Journal reading habits of internists. J Gen Intern Med 2000;15:881– 884. 6. DuBiner H, Cooke D, Dirks M, Stewart WC, VanDenburgh AM, Felix C. Efficacy and safety of bimatoprost in patients with elevated intraocular pressure: a 30-day comparison with latanoprost. Surv Ophthalmol 2001;45:S353–360. 7. Tukey JW. Some thoughts on clinical trials, especially problems of multiplicity. Science 1977;198:679 – 684.
2
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
JANUARY 2009