Comment from the editors

Abstract

Pharmaceutical influence on clinical science and practice: A double-edged swordAt the same time pharmaceutical companies are rapidly advancing basic science, clinical research, and patient care and are supporting academic educational initiatives, unprincipled members of the industry are encroaching on our professional ethics, thereby endangering the credibility that is essential for effective clinical research and patient interactions. The lay press is replete with well-documented industry exploitation of our greed and desire for fame/power, as well as our desire to provide the best care for our patients. This negative pharmaceutical influence is manifest by selective reporting of clinical trials that suppresses negative results and toxicity; biased presentations at continuing medical education (CME) courses, self-serving marketing by pharmaceutical “reps,” frequently for off-label indications; using highly compensated “thought leaders” to influence clinical practice; buying audience with gifts of dubious educational value; and direct marketing of drugs to patients.Successful evidence-based medicine depends on publication of all clinical trials, including those with negative outcomes. Selective disclosure of clinical trials has important consequences. In June, a lawsuit filed by the New York State Attorney General, Elliot Spitzer, alleged suppression of publication of 4 clinical trials that showed that Paxil is not effective in treating depression in children and adolescents and that showed a possible increase in suicidal risk. To their credit, the company responded by publishing results of these studies on a Web site. More relevant to our specialty, a recent meta-analysis by Hanauer and Stromberg (Clin Gastroenterol Hepatol 2004;2:379–388) that included data from 2 previously completed but unpublished randomized clinical trials showed only a minor, probably clinically insignificant, benefit of mesalamine in Crohn’s disease, which contradicts the conclusion of the single published trial that suggested a dose-dependent benefit. The consequences of not publishing these 2 negative but well-designed industry-sponsored studies is eloquently discussed by an accompanying editorial by Brian Feagan (Clin Gastroenterol Hepatol 2004;2:376–378). Although the bias toward publishing positive trials is widely attributed to the peer-review process, recent studies indicate that publication bias rests more appropriately on the author and the sponsoring drug company. Of considerable interest, a strong association (P < 0.001) exists between the frequency of publishing positive versus negative data and a declared conflict of interest by at least 1 author (Gen Intern Med 2004;19:51–56). Conflicted publications reported 85% positive and less than 2% negative results, whereas publications from authors with no reported conflicts of interest reported near equal positive (41%) and negative (36%) results. Similar conclusions were reached in an independent study by Lexchin et al. (BMJ 2003;326:1167–1170), who noted that studies sponsored by pharmaceutical companies were more likely to have results favoring the sponsor (odds ratio, 4.05) and have an overall lower rate of publication than studies sponsored by other sources. The involvement of industry employees in study design, data analysis, and manuscript preparation creates complexities for publication. Although industry clinical researchers bring high levels of sophistication to experimental design that are necessary to comply with regulatory issues, influences by marketing specialists introduce the opportunity to emphasize positive outcomes and minimize toxicities. Obviously, selective reporting of positive therapeutic trials and incomplete disclosure of clinically significant toxicities negatively impacts effective clinical practice.More difficult to document, but equally destructive to patient treatment, is the covert affiliation of visible “thought leaders” with a pharmaceutical compound. Lucrative consulting agreements, speaker’s fees, and the opportunity to be widely publicized can persuade a well-meaning investigator, academic leader, or locally prominent clinician to favor one of several competing treatment alternatives. Such biased presentations by a chosen “poster child” are most obvious during the rapidly proliferating single company-sponsored symposia in conjunction with national meetings, but can more covertly influence published reviews, position statements, Food and Drug Administration panel presentations, and our daily clinical practice. Pharmaceutical representatives are quick to report that, “Dr. X uses our compound.” Although rarely revealed in public, an alarming number of reviews, monographs, and letters to the editors are written by professional editors employed by companies, with trivial input from the listed author(s). Likewise, speakers, particularly those who were not involved in the original research in an area, are frequently presented with very sophisticated slides constructed by the company, which chooses studies and draws conclusions for presentation. Katz et al. (J Contin Educ Health Prof 2002;22:43–54) studied content of single-sponsored symposia versus university-designed CME courses and, not surprisingly, showed that industry-sponsored programs had a more narrow topic selection. Undoubtedly, the messages delivered at such symposia are also more focused on supporting the sponsor’s product.Unfortunately, pharmaceutical influences are not confined to a few highly visible “thought leaders,” but are directed toward individual practitioners and trainees. According to a June 27, 2004, article in the New York Times, multiple industry titans are under investigation for offering high volume practitioners “consulting agreements” or opportunities to perform “post marketing research” that are thinly veiled commitments to exclusively prescribe specific medications. The global pharmaceutical industry is a $400 billion per year enterprise with extreme competition for lucrative markets in viral hepatitis, acid/peptic disease, and inflammatory bowel diseases, which invites abuse. Courting of prescription-writing clinicians by distribution of gifts and meals begins in medical school and continues during all phases of training. By the time a gastrointestinal fellow enters practice, he or she is thoroughly indoctrinated into interacting with very personable (and attractive) pharmaceutical representatives who become valuable sources of information on new drugs as well as a continued supply of “free” gifts. Academia is not immune to these influences and, in many respects, is responsible for this mindset because of its dependence on lunches for staff, support for outside speakers (frequently drawn from approved company lists), travel funds for trainees and faculty to national meetings, and lucrative industry-sponsored preclinical and clinical trials that rarely compare alternative agents or address a hypothesis but, rather, are designed to promote approval or clinical use of a particular compound.Many benefits have been derived from pharmaceutical company support of medical research and education. Industry-supported basic, clinical, and applied research has led to dramatic advances that have changed the practice of gastroenterology and hepatology, including endoscopy, histamine receptor 2 (H2) blockers, proton-pump inhibitors, interferon, infliximab, serotonin uptake inhibitors, and targeted delivery of 5-ASA and corticosteroids. Pharmaceutical companies have generously supported education and research by unrestricted donations to medical schools, medical foundations, and local and national professional societies. Some of the highest quality basic research is taking place within the pharmaceutical industry, in which resources far outstrip those available in academic laboratories. These benefits and the economic impact of this industry are undeniable and extremely important but, unfortunately, are frequently overshadowed by the widely publicized abuses of a few renegade members.Because this enormous power can be abused, potential conflicts must be recognized and guarded against. This can most effectively be done by adherence to the recently published guidelines for individual physicians and organizations by the American College of Physicians and American Society for Internal Medicine (Ann Intern Med 2002;136:396–402, 403–406). Real or potential conflicts of interest must be fully disclosed and honestly discussed. The peer-review process must prevent post hoc analysis and insist on adherence to primary treatment outcomes of therapeutic trials. Prominent clinical investigators have advocated that original study protocols be submitted with the manuscript to facilitate critical peer review. Gastroenterology conforms with the editors of other biomedical journals in requiring that academic principle investigators of a study have access to original data and have no restrictions on publication, although this critical control is exceedingly difficult to enforce. Ongoing clinical trials should be centrally registered, and both positive and negative results entered into a public access database. This database must be designed and implemented by the Food and Drug Administration or other authoritative agency. CME programs must be designed and controlled by nonaffiliated organizers and sponsored by multiple parties to avoid biases. We all must resist opportunities to align ourselves with companies with vested interests, and commit to unbiased presentations and publications that discuss the relative benefits, risks, and costs of competing therapeutic approaches. Such actions will harness the considerable benefits of the pharmaceutical industry and reverse the insidious integration of companies with vested interests into our daily practice, clinical investigation, and medical education. Universal application of these principles could even decrease drug costs to our patients, because advertising and promotion costs far outstrip those of research and development (Lancet 2002;360:1682–1684) and probably account for discrepancies in drug costs in the United States and Canada. Pharmaceutical influence on clinical science and practice: A double-edged swordAt the same time pharmaceutical companies are rapidly advancing basic science, clinical research, and patient care and are supporting academic educational initiatives, unprincipled members of the industry are encroaching on our professional ethics, thereby endangering the credibility that is essential for effective clinical research and patient interactions. The lay press is replete with well-documented industry exploitation of our greed and desire for fame/power, as well as our desire to provide the best care for our patients. This negative pharmaceutical influence is manifest by selective reporting of clinical trials that suppresses negative results and toxicity; biased presentations at continuing medical education (CME) courses, self-serving marketing by pharmaceutical “reps,” frequently for off-label indications; using highly compensated “thought leaders” to influence clinical practice; buying audience with gifts of dubious educational value; and direct marketing of drugs to patients.Successful evidence-based medicine depends on publication of all clinical trials, including those with negative outcomes. Selective disclosure of clinical trials has important consequences. In June, a lawsuit filed by the New York State Attorney General, Elliot Spitzer, alleged suppression of publication of 4 clinical trials that showed that Paxil is not effective in treating depression in children and adolescents and that showed a possible increase in suicidal risk. To their credit, the company responded by publishing results of these studies on a Web site. More relevant to our specialty, a recent meta-analysis by Hanauer and Stromberg (Clin Gastroenterol Hepatol 2004;2:379–388) that included data from 2 previously completed but unpublished randomized clinical trials showed only a minor, probably clinically insignificant, benefit of mesalamine in Crohn’s disease, which contradicts the conclusion of the single published trial that suggested a dose-dependent benefit. The consequences of not publishing these 2 negative but well-designed industry-sponsored studies is eloquently discussed by an accompanying editorial by Brian Feagan (Clin Gastroenterol Hepatol 2004;2:376–378). Although the bias toward publishing positive trials is widely attributed to the peer-review process, recent studies indicate that publication bias rests more appropriately on the author and the sponsoring drug company. Of considerable interest, a strong association (P < 0.001) exists between the frequency of publishing positive versus negative data and a declared conflict of interest by at least 1 author (Gen Intern Med 2004;19:51–56). Conflicted publications reported 85% positive and less than 2% negative results, whereas publications from authors with no reported conflicts of interest reported near equal positive (41%) and negative (36%) results. Similar conclusions were reached in an independent study by Lexchin et al. (BMJ 2003;326:1167–1170), who noted that studies sponsored by pharmaceutical companies were more likely to have results favoring the sponsor (odds ratio, 4.05) and have an overall lower rate of publication than studies sponsored by other sources. The involvement of industry employees in study design, data analysis, and manuscript preparation creates complexities for publication. Although industry clinical researchers bring high levels of sophistication to experimental design that are necessary to comply with regulatory issues, influences by marketing specialists introduce the opportunity to emphasize positive outcomes and minimize toxicities. Obviously, selective reporting of positive therapeutic trials and incomplete disclosure of clinically significant toxicities negatively impacts effective clinical practice.More difficult to document, but equally destructive to patient treatment, is the covert affiliation of visible “thought leaders” with a pharmaceutical compound. Lucrative consulting agreements, speaker’s fees, and the opportunity to be widely publicized can persuade a well-meaning investigator, academic leader, or locally prominent clinician to favor one of several competing treatment alternatives. Such biased presentations by a chosen “poster child” are most obvious during the rapidly proliferating single company-sponsored symposia in conjunction with national meetings, but can more covertly influence published reviews, position statements, Food and Drug Administration panel presentations, and our daily clinical practice. Pharmaceutical representatives are quick to report that, “Dr. X uses our compound.” Although rarely revealed in public, an alarming number of reviews, monographs, and letters to the editors are written by professional editors employed by companies, with trivial input from the listed author(s). Likewise, speakers, particularly those who were not involved in the original research in an area, are frequently presented with very sophisticated slides constructed by the company, which chooses studies and draws conclusions for presentation. Katz et al. (J Contin Educ Health Prof 2002;22:43–54) studied content of single-sponsored symposia versus university-designed CME courses and, not surprisingly, showed that industry-sponsored programs had a more narrow topic selection. Undoubtedly, the messages delivered at such symposia are also more focused on supporting the sponsor’s product.Unfortunately, pharmaceutical influences are not confined to a few highly visible “thought leaders,” but are directed toward individual practitioners and trainees. According to a June 27, 2004, article in the New York Times, multiple industry titans are under investigation for offering high volume practitioners “consulting agreements” or opportunities to perform “post marketing research” that are thinly veiled commitments to exclusively prescribe specific medications. The global pharmaceutical industry is a $400 billion per year enterprise with extreme competition for lucrative markets in viral hepatitis, acid/peptic disease, and inflammatory bowel diseases, which invites abuse. Courting of prescription-writing clinicians by distribution of gifts and meals begins in medical school and continues during all phases of training. By the time a gastrointestinal fellow enters practice, he or she is thoroughly indoctrinated into interacting with very personable (and attractive) pharmaceutical representatives who become valuable sources of information on new drugs as well as a continued supply of “free” gifts. Academia is not immune to these influences and, in many respects, is responsible for this mindset because of its dependence on lunches for staff, support for outside speakers (frequently drawn from approved company lists), travel funds for trainees and faculty to national meetings, and lucrative industry-sponsored preclinical and clinical trials that rarely compare alternative agents or address a hypothesis but, rather, are designed to promote approval or clinical use of a particular compound.Many benefits have been derived from pharmaceutical company support of medical research and education. Industry-supported basic, clinical, and applied research has led to dramatic advances that have changed the practice of gastroenterology and hepatology, including endoscopy, histamine receptor 2 (H2) blockers, proton-pump inhibitors, interferon, infliximab, serotonin uptake inhibitors, and targeted delivery of 5-ASA and corticosteroids. Pharmaceutical companies have generously supported education and research by unrestricted donations to medical schools, medical foundations, and local and national professional societies. Some of the highest quality basic research is taking place within the pharmaceutical industry, in which resources far outstrip those available in academic laboratories. These benefits and the economic impact of this industry are undeniable and extremely important but, unfortunately, are frequently overshadowed by the widely publicized abuses of a few renegade members.Because this enormous power can be abused, potential conflicts must be recognized and guarded against. This can most effectively be done by adherence to the recently published guidelines for individual physicians and organizations by the American College of Physicians and American Society for Internal Medicine (Ann Intern Med 2002;136:396–402, 403–406). Real or potential conflicts of interest must be fully disclosed and honestly discussed. The peer-review process must prevent post hoc analysis and insist on adherence to primary treatment outcomes of therapeutic trials. Prominent clinical investigators have advocated that original study protocols be submitted with the manuscript to facilitate critical peer review. Gastroenterology conforms with the editors of other biomedical journals in requiring that academic principle investigators of a study have access to original data and have no restrictions on publication, although this critical control is exceedingly difficult to enforce. Ongoing clinical trials should be centrally registered, and both positive and negative results entered into a public access database. This database must be designed and implemented by the Food and Drug Administration or other authoritative agency. CME programs must be designed and controlled by nonaffiliated organizers and sponsored by multiple parties to avoid biases. We all must resist opportunities to align ourselves with companies with vested interests, and commit to unbiased presentations and publications that discuss the relative benefits, risks, and costs of competing therapeutic approaches. Such actions will harness the considerable benefits of the pharmaceutical industry and reverse the insidious integration of companies with vested interests into our daily practice, clinical investigation, and medical education. Universal application of these principles could even decrease drug costs to our patients, because advertising and promotion costs far outstrip those of research and development (Lancet 2002;360:1682–1684) and probably account for discrepancies in drug costs in the United States and Canada. At the same time pharmaceutical companies are rapidly advancing basic science, clinical research, and patient care and are supporting academic educational initiatives, unprincipled members of the industry are encroaching on our professional ethics, thereby endangering the credibility that is essential for effective clinical research and patient interactions. The lay press is replete with well-documented industry exploitation of our greed and desire for fame/power, as well as our desire to provide the best care for our patients. This negative pharmaceutical influence is manifest by selective reporting of clinical trials that suppresses negative results and toxicity; biased presentations at continuing medical education (CME) courses, self-serving marketing by pharmaceutical “reps,” frequently for off-label indications; using highly compensated “thought leaders” to influence clinical practice; buying audience with gifts of dubious educational value; and direct marketing of drugs to patients. Successful evidence-based medicine depends on publication of all clinical trials, including those with negative outcomes. Selective disclosure of clinical trials has important consequences. In June, a lawsuit filed by the New York State Attorney General, Elliot Spitzer, alleged suppression of publication of 4 clinical trials that showed that Paxil is not effective in treating depression in children and adolescents and that showed a possible increase in suicidal risk. To their credit, the company responded by publishing results of these studies on a Web site. More relevant to our specialty, a recent meta-analysis by Hanauer and Stromberg (Clin Gastroenterol Hepatol 2004;2:379–388) that included data from 2 previously completed but unpublished randomized clinical trials showed only a minor, probably clinically insignificant, benefit of mesalamine in Crohn’s disease, which contradicts the conclusion of the single published trial that suggested a dose-dependent benefit. The consequences of not publishing these 2 negative but well-designed industry-sponsored studies is eloquently discussed by an accompanying editorial by Brian Feagan (Clin Gastroenterol Hepatol 2004;2:376–378). Although the bias toward publishing positive trials is widely attributed to the peer-review process, recent studies indicate that publication bias rests more appropriately on the author and the sponsoring drug company. Of considerable interest, a strong association (P < 0.001) exists between the frequency of publishing positive versus negative data and a declared conflict of interest by at least 1 author (Gen Intern Med 2004;19:51–56). Conflicted publications reported 85% positive and less than 2% negative results, whereas publications from authors with no reported conflicts of interest reported near equal positive (41%) and negative (36%) results. Similar conclusions were reached in an independent study by Lexchin et al. (BMJ 2003;326:1167–1170), who noted that studies sponsored by pharmaceutical companies were more likely to have results favoring the sponsor (odds ratio, 4.05) and have an overall lower rate of publication than studies sponsored by other sources. The involvement of industry employees in study design, data analysis, and manuscript preparation creates complexities for publication. Although industry clinical researchers bring high levels of sophistication to experimental design that are necessary to comply with regulatory issues, influences by marketing specialists introduce the opportunity to emphasize positive outcomes and minimize toxicities. Obviously, selective reporting of positive therapeutic trials and incomplete disclosure of clinically significant toxicities negatively impacts effective clinical practice. More difficult to document, but equally destructive to patient treatment, is the covert affiliation of visible “thought leaders” with a pharmaceutical compound. Lucrative consulting agreements, speaker’s fees, and the opportunity to be widely publicized can persuade a well-meaning investigator, academic leader, or locally prominent clinician to favor one of several competing treatment alternatives. Such biased presentations by a chosen “poster child” are most obvious during the rapidly proliferating single company-sponsored symposia in conjunction with national meetings, but can more covertly influence published reviews, position statements, Food and Drug Administration panel presentations, and our daily clinical practice. Pharmaceutical representatives are quick to report that, “Dr. X uses our compound.” Although rarely revealed in public, an alarming number of reviews, monographs, and letters to the editors are written by professional editors employed by companies, with trivial input from the listed author(s). Likewise, speakers, particularly those who were not involved in the original research in an area, are frequently presented with very sophisticated slides constructed by the company, which chooses studies and draws conclusions for presentation. Katz et al. (J Contin Educ Health Prof 2002;22:43–54) studied content of single-sponsored symposia versus university-designed CME courses and, not surprisingly, showed that industry-sponsored programs had a more narrow topic selection. Undoubtedly, the messages delivered at such symposia are also more focused on supporting the sponsor’s product. Unfortunately, pharmaceutical influences are not confined to a few highly visible “thought leaders,” but are directed toward individual practitioners and trainees. According to a June 27, 2004, article in the New York Times, multiple industry titans are under investigation for offering high volume practitioners “consulting agreements” or opportunities to perform “post marketing research” that are thinly veiled commitments to exclusively prescribe specific medications. The global pharmaceutical industry is a $400 billion per year enterprise with extreme competition for lucrative markets in viral hepatitis, acid/peptic disease, and inflammatory bowel diseases, which invites abuse. Courting of prescription-writing clinicians by distribution of gifts and meals begins in medical school and continues during all phases of training. By the time a gastrointestinal fellow enters practice, he or she is thoroughly indoctrinated into interacting with very personable (and attractive) pharmaceutical representatives who become valuable sources of information on new drugs as well as a continued supply of “free” gifts. Academia is not immune to these influences and, in many respects, is responsible for this mindset because of its dependence on lunches for staff, support for outside speakers (frequently drawn from approved company lists), travel funds for trainees and faculty to national meetings, and lucrative industry-sponsored preclinical and clinical trials that rarely compare alternative agents or address a hypothesis but, rather, are designed to promote approval or clinical use of a particular compound. Many benefits have been derived from pharmaceutical company support of medical research and education. Industry-supported basic, clinical, and applied research has led to dramatic advances that have changed the practice of gastroenterology and hepatology, including endoscopy, histamine receptor 2 (H2) blockers, proton-pump inhibitors, interferon, infliximab, serotonin uptake inhibitors, and targeted delivery of 5-ASA and corticosteroids. Pharmaceutical companies have generously supported education and research by unrestricted donations to medical schools, medical foundations, and local and national professional societies. Some of the highest quality basic research is taking place within the pharmaceutical industry, in which resources far outstrip those available in academic laboratories. These benefits and the economic impact of this industry are undeniable and extremely important but, unfortunately, are frequently overshadowed by the widely publicized abuses of a few renegade members. Because this enormous power can be abused, potential conflicts must be recognized and guarded against. This can most effectively be done by adherence to the recently published guidelines for individual physicians and organizations by the American College of Physicians and American Society for Internal Medicine (Ann Intern Med 2002;136:396–402, 403–406). Real or potential conflicts of interest must be fully disclosed and honestly discussed. The peer-review process must prevent post hoc analysis and insist on adherence to primary treatment outcomes of therapeutic trials. Prominent clinical investigators have advocated that original study protocols be submitted with the manuscript to facilitate critical peer review. Gastroenterology conforms with the editors of other biomedical journals in requiring that academic principle investigators of a study have access to original data and have no restrictions on publication, although this critical control is exceedingly difficult to enforce. Ongoing clinical trials should be centrally registered, and both positive and negative results entered into a public access database. This database must be designed and implemented by the Food and Drug Administration or other authoritative agency. CME programs must be designed and controlled by nonaffiliated organizers and sponsored by multiple parties to avoid biases. We all must resist opportunities to align ourselves with companies with vested interests, and commit to unbiased presentations and publications that discuss the relative benefits, risks, and costs of competing therapeutic approaches. Such actions will harness the considerable benefits of the pharmaceutical industry and reverse the insidious integration of companies with vested interests into our daily practice, clinical investigation, and medical education. Universal application of these principles could even decrease drug costs to our patients, because advertising and promotion costs far outstrip those of research and development (Lancet 2002;360:1682–1684) and probably account for discrepancies in drug costs in the United States and Canada. The author thanks David Brenner for editorial comments and Bill Sandborn and Bob Sandler for helpful discussions and suggestions.