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Evaluation of Conflict of Interest in Economic Analyses of New Drugs Used in Oncology
Mark Friedberg, BA;
Bernard Saffran, PhD;
Tammy J. Stinson, MS;
Wendy Nelson, PhD;
Charles L. Bennett, MD, PhD
JAMA. 1999;282:1453-1457.
ABSTRACT
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Context Recent studies have found that when investigators have financial relationships with pharmaceutical or product manufacturers, they are less likely to criticize the safety or efficacy of these agents. The effects of health economics research on pharmaceutical company revenue make drug investigations potentially vulnerable to this bias.
Objective To determine whether there is an association between pharmaceutical industry sponsorship and economic assessment of oncology drugs.
Design MEDLINE and HealthSTAR databases (1988-1998) were searched for original English-language research articles of cost or cost-effectiveness analyses of 6 oncology drugs in 3 new drug categories (hematopoietic colony-stimulating factors, serotonin antagonist antiemetics, and taxanes), yielding 44 eligible articles. Two investigators independently abstracted each article based on specific criteria.
Main Outcome Measure Relationships between funding source and (1) qualitative cost assessment (favorable, neutral, or unfavorable) and (2) qualitative conclusions that overstated quantitative results.
Results Pharmaceutical company–sponsored studies were less likely than nonprofit-sponsored studies to report unfavorable qualitative conclusions (1/20 [5%] vs 9/24 [38%]; P=.04), whereas overstatements of quantitative results were not significantly different in pharmaceutical company–sponsored (6/20 [30%]) vs nonprofit-sponsored (3/24 [13%]) studies (P=.26).
Conclusions Although we did not identify bias in individual studies, these findings indicate that pharmaceutical company sponsorship of economic analyses is associated with reduced likelihood of reporting unfavorable results.
INTRODUCTION
Financial conflict of interest is a pressing issue for the medical research community.1-2 Physicians' economic ties to tobacco, alcohol, baby formula, and pharmaceutical companies have all been criticized as possible nonscientific influences on medical research.3-6 Recent studies of research on calcium channel antagonists in cardiology, nonsteroidal anti-inflammatory drugs for the treatment of arthritis, and the health effects of secondhand smoke all found that physicians with financial ties to manufacturers were significantly less likely to criticize the safety or efficacy of these agents.7-9 Similarly, a study of clinical trial publications determined that there was a significant association between positive results in general internal medicine clinical trials and funding from a pharmaceutical manufacturer.10
While the debate over financial conflict of interest has surrounded issues of clinical efficacy and safety, only 1 prior study has addressed concerns related to reports on cost-effectiveness.11 In that study, Azimi and Welch11 reported that industry-financed cost-effectiveness analyses were more likely to support additional expenditures with investigational drugs than standard treatments. To further examine the existing pharmacoeconomic literature, we evaluated cost studies for 3 recent breakthrough areas in oncology: hematopoietic colony-stimulating factors, serotonin antagonist antiemetics, and taxanes. Economic studies of these agents have reported varying assessments of costs and cost-effectiveness.12-17 This study was designed to determine whether the apparent financially motivated bias seen in clinical efficacy and safety evaluations is also evident in economic analyses in oncology.
The major objective of this study was to determine whether there was an association between pharmaceutical industry sponsorship and economic assessments of breakthrough oncology drugs. The following questions were addressed: were pharmaceutical company–funded economic studies more likely than nonprofit-funded studies to report favorable qualitative assessments and less likely to report unfavorable qualitative assessments? and were pharmaceutical company–sponsored studies more likely than nonprofit-funded studies to state qualitatively favorable conclusions despite neutral or unfavorable quantitative results?
METHODS
Economic analyses of 6 recently marketed breakthrough cancer drugs in 3 categories were chosen. The agents included hematopoietic growth factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte-macrophage colony-stimulating factor [GM-CSF]), serotonin antagonist antiemetics (ondansetron hydrochloride and granisetron), and taxane chemotherapy agents (paclitaxel and docetaxel). These drugs were chosen because their cost-effectiveness is controversial, and they account for a large fraction of total pharmaceutical expenditures in many hospital pharmacies. Clinical reports have demonstrated efficacy in specific settings, but high acquisition and administration costs have raised concern about the widespread use of these agents.
We searched the MEDLINE (1988-1998) and HealthSTAR (1988-1998) databases to identify original research articles that contained an economic analysis of 1 or more of the study drugs. The following terms were searched: cost(s), cost-effective(ness), economic(s), dollar(s), pharmacoeconomic(s), and cost-benefit. Drugs were searched under generic and brand names. Abstracts, letters, editorials, review articles, and non–English-language articles were excluded. Abstracts from the remaining articles were reviewed, and all articles including an actual analysis of costs were identified. This search yielded 54 articles, of which 8 were head-to-head comparisons between drugs in a given category (eg, G-CSF vs GM-CSF) and 46 were comparisons with placebo or standard treatment. Head-to-head comparisons were excluded because they could not be classified according to our criteria; ie, the results would always be either favorable or neutral for 1 or the other of the study drugs. Another 2 articles18-19 were excluded because we were unable to obtain information about the funding source, despite repeated requests. Of the 44 articles studied, there were 28 articles for hematopoietic colony-stimulating factors,12-13,20-45 11 articles for antiemetics,14-15,46-54 and 5 articles for taxanes.16-17,55-57 The types of analyses included were cost-minimization or cost-identification (a comparison of the costs of treatment for 2 different agents with similar efficacy or outcomes) and cost-effectiveness (comparison of the costs of treatment for 2 agents normalized by their effectiveness, typically reported as cost per life-year gained). All of the articles fit 1 of these types, based on generally accepted definitions.58-59
Two investigators (M.F. and W.N.) independently abstracted information from each of the articles based on distinct, written, preset criteria. Information was collected on (1) the qualitative conclusion as stated in the abstract or manuscript conclusion, (2) the quantitative numerical results, (3) the timing of the study, and (4) the funding source.
Qualitative conclusions were rated according to the following criteria: favorable (the new drug "reduces costs" or is "cost-effective"), neutral (the new drug "is cost equivalent" or "may be cost-effective," or "does not require additional costs" over standard therapy), or unfavorable (the new drug has "higher costs" or is "not cost-effective"). Whenever the 2 investigators disagreed over an article's qualitative conclusion, a third investigator made the final decision.
Quantitative numerical results were also rated as favorable, neutral, or unfavorable. For cost-minimization studies, numerical results were classified as favorable when the costs of use of the new drug were less than standard treatment, neutral when there was no difference between the new drug and the standard, and unfavorable when the costs of use of the new drug were more than standard treatment. The total cost of treatment for each arm of the study was compared, including the cost of the study drug. When tests of statistical significance were available, significant differences were interpreted as favorable or unfavorable. Statistically insignificant differences were interpreted as neutral. For articles that did not include statistical analyses (typically, decision analyses), robust differences were interpreted as favorable or unfavorable. Nonrobust differences (which reversed direction under sensitivity analyses) were interpreted as neutral. For cost-effectiveness studies, any cost estimate of less than $50,000 per life-year gained was considered favorable, as is generally accepted in the literature.60 More expensive results were considered unfavorable.
Study timing was interpreted as either prospective (the study was initiated alongside the clinical trial) or retrospective (the economic study was begun after the results of the clinical study were known).
Funding source was abstracted after recording a study's qualitative conclusion, quantitative results, and timing. Investigators were not specifically blinded as to funding source during abstraction. Articles were classified as either pharmaceutical company–sponsored or nonprofit-sponsored (government agency, professional organization, nonprofit foundation, or academic institution). For publications not including an acknowledgment of funding (17/46), first and last authors were contacted via mail, e-mail, and/or telephone and queried regarding the funding source of their study. Authors from 13 of 17 articles replied that their studies were either not externally funded or funded by nonprofit sources, while authors of 2 of 17 articles reported that their studies were funded by pharmaceutical companies. Authors of the remaining 2 articles18-19 did not reply, and their studies were not included in our analyses.
Relationships between funding source and (1) qualitative conclusion (favorable, neutral, or unfavorable), (2) overstatement of results (a favorable qualitative conclusion despite neutral or unfavorable quantitative results or a neutral qualitative conclusion despite unfavorable quantitative results), (3) study agent (hematopoietic growth factor, antiemetic, or taxane), (4) study timing (prospective or retrospective), (5) analysis type (cost minimization or cost-effectiveness), (6) journal type (peer-reviewed or non–peer-reviewed), and (7) author affiliations (all academic, or at least 1 pharmaceutical company or consulting firm employee) were analyzed using Fisher exact tests (for 2 x 2 tables with an expected cell value less than 5) or Pearson  2 tests. A 2-sided P value (against the null hypothesis of no relationship between conclusion and funding source) less than .05 was considered significant.
RESULTS
Of the 44 articles, 20 were funded by pharmaceutical companies and 24 by nonprofit organizations. For those studies funded by pharmaceutical companies, the funding source was always the manufacturer of the investigational drug. Approximately 65% of studies analyzed hematopoietic growth factors, 25% antiemetics, and 10% taxanes (Table 1). This distribution was similar for both pharmaceutical- and nonprofit-sponsored studies. Study timing, analysis type, and journal type also did not differ significantly by funding source. All authors of nonprofit-sponsored studies had academic affiliations, whereas 40% of pharmaceutical company–sponsored studies had at least 1 author with a pharmaceutical company or consulting firm affiliation (divided evenly between pharmaceutical company and consulting firm employees).
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Table. Study Set Characteristics and Conclusions*
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There was a statistically significant relationship between funding source and qualitative conclusions (P=.04). Unfavorable conclusions were reached by 38% (9/24) of nonprofit-sponsored studies but by only 5% (1/20) of pharmaceutical company–sponsored studies (Table 1). Reports including only authors who had an academic affiliation appeared more likely to report unfavorable conclusions (28% [10/36]) than those including pharmaceutical or consulting firm employees (0% [0/8]), although this difference was not significant (P=.18). The 2 investigators agreed on the classification of qualitative conclusions in 87% of the articles, with the third investigator determining the classification of the remaining 13%.
In addition, pharmaceutical company–sponsored studies were somewhat more likely than nonprofit-sponsored studies to overstate quantitative results; ie, a favorable qualitative conclusion when quantitative results were neutral or unfavorable, or a neutral conclusion when quantitative results were unfavorable (30% [6/20] vs 13% [3/24]), although this finding was not statistically significant (P=.26).
COMMENT
This study investigated financial conflicts of interest in the debate over economic analyses of breakthrough oncology drugs. We found a significant association between authors' stated qualitative conclusions regarding the costs and cost-effectiveness of these drugs and study sponsorship by the drugs' manufacturers. Studies funded by pharmaceutical companies were nearly 8 times less likely to reach unfavorable qualitative conclusions than nonprofit-funded studies and 1.4 times more likely to reach favorable qualitative conclusions. We also determined that 1 in 5 articles contained qualitative overstatements of quantitative results.
A number of hypotheses can help explain our findings. First, the retrospective methods used in 89% of our sample studies allow investigators and pharmaceutical companies "early looks" at clinical results and associated resource profiles. These early clinical data can be used to selectively identify the trials most likely to yield positive outcomes, and the pharmaceutical companies can fund economic studies accordingly and therefore, can potentially exercise a limited power to censor unfavorable studies simply by withholding financial support.
Second, there is an evident bias in the body of pharmacoeconomics research (also seen in other areas of medical research) toward the publication of studies with "positive" results. Regardless of funding source, studies with unfavorable preliminary evidence are less likely to be completed, less likely to be submitted for peer review, and, once submitted, less likely to be published.61
Third, pharmaceutical companies can influence research in a variety of ways. Studies may be funded through unrestricted research grants, educational funds, or consultancies (paid directly to investigators). These may include contractual agreements requiring pharmaceutical company review of manuscripts before being submitted for publication. Researchers also may receive funding from the same companies in the form of honoraria or travel awards for scientific meetings and have equity interests in companies and profit directly from increased drug sales.62 It is possible that these factors may result in some unconscious bias (perhaps when qualitatively interpreting results) that could influence study conclusions.
Fourth, the pharmaceutical companies can collaborate directly with investigators in devising protocols for economic analyses and indirectly shape the economic evaluation criteria.
Our study has several limitations. First, we considered only 1 type of economic relationship between pharmaceutical companies and researchers: direct funding of the analysis reported. Second, our ability to investigate direct financial sponsorship of the individual studies was limited because we were unable to review contracts or grants. While we used published information and direct communication with authors, the nature and degree of the financial relationship were not investigated.
The correlation between pharmaceutical company funding and favorable study conclusions might add to public uncertainty regarding company-sponsored medical research.63-64 Although other sources of funds for pharmacoeconomic studies are needed, limiting the publication of pharmaceutical company–sponsored studies is probably not feasible or practical. Pharmaceutical companies provide valuable resources to many areas of academic medicine and are a primary source of funding for pharmacoeconomic studies.7, 58 To improve the credibility of economic analyses, policies promoting full disclosure of all financial interests should be pursued. Conducting more prospective pharmacoeconomic analyses (in conjunction with phase 3 trials) would also increase credibility by eliminating the opportunity for selective funding based on clinical results.65 Finally, pharmacoeconomic literature would be more balanced if managed care organizations, government agencies, and nonprofit groups increased their support for high-quality prospective pharmacoeconomic studies.
AUTHOR INFORMATION
Financial Disclosure: Dr Bennett has previously or concurrently received research grants from Amgen, Bristol-Myers Squibb, Glaxo Burroughs Wellcome, Immunex, Schering Plough, and SmithKline Beecham; and has served as a speaker's consultant for Amgen, Immunex, and Schering Plough, and received honoraria for this purpose. Ms Stinson has served as a consultant in the preparation of manuscripts for Bristol-Myers Squibb, Immunex, and Schering Plough.
Funding/Support: The data collection efforts for this study were funded by an unrestricted grant from Amgen Inc, Thousand Oaks, Calif, as part of a larger, ongoing study. The sponsor had a contractual right to review and comment on manuscripts and abstracts prior to submission.
Corresponding Author and Reprints: Charles L. Bennett, MD, PhD, Lakeside VAMC, 400 E Ontario Ave, Chicago, IL 60611 (e-mail: cbenne{at}nwu.edu).
Author Affiliations: Institute for Health Services Research and Policy Studies (Dr Bennett) and Division of Hematology/Oncology, Northwestern University (Mr Friedberg and Drs Nelson and Bennett) and Lakeside Veterans Affairs Medical Center (Ms Stinson and Dr Bennett), Chicago, Ill; and the Department of Economics, Swarthmore College, Swarthmore, Pa (Dr Saffran).
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Commercially Funded and United States-Based Research Is More Likely to Be Published; Good-Quality Studies with Negative Outcomes Are Not
Lynch et al.
JBJS 2007;89:1010-1018.
ABSTRACT
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Interpreting the Economic Literature in Oncology
Grusenmeyer and Wong
JCO 2007;25:196-202.
ABSTRACT
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A piece of my mind. Swan's way.
Blank
JAMA 2006;296:1041-1042.
FULL TEXT
Transparency in Communication: An Examination of Communication Journals' Conflicts-of-Interest Policies
Soley and Feldner
Journal of Communication Inquiry 2006;30:209-228.
ABSTRACT
When the Risk of Febrile Neutropenia Is 20%, Prophylactic Colony-Stimulating Factor Use Is Clinically Effective, but Is It Cost-Effective?
Adams et al.
JCO 2006;24:2975-2977.
FULL TEXT
Editor's Note: Industry Support of Articles Published in Mayo Clinic Proceedings
Lanier
Mayo Clin Proc. 2006;81:851-852.
FULL TEXT
Financial Disclosures of Scientific Papers Presented at the 2003 RSNA Annual Meeting: Association with Reporting of Non-Food and Drug Administration-approved Uses of Industry Products
Brown et al.
Radiology 2006;239:849-855.
ABSTRACT
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How NICE may be outflanked.
Ferner and McDowell
BMJ 2006;332:1268-1271.
FULL TEXT
Bias in published cost effectiveness studies: systematic review
Bell et al.
BMJ 2006;332:699-703.
ABSTRACT
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Industry Sponsorship and Financial Conflict of Interest in the Reporting of Clinical Trials in Psychiatry
Perlis et al.
Am. J. Psychiatry 2005;162:1957-1960.
ABSTRACT
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Adding Value to Evidence-Based Clinical Guidelines
O'Connor
JAMA 2005;294:741-743.
FULL TEXT
The Contract Research Organization and the Commercialization of Scientific Research
Mirowski and Van Horn
Social Studies of Science 2005;35:503-548.
ABSTRACT
Conflict of interest in psychiatry
Ahmer et al.
Psychiatr. Bull. 2005;29:302-304.
ABSTRACT
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Report of the National Heart, Lung, and Blood Institute Working Group on Outcomes Research in Cardiovascular Disease
Krumholz et al.
Circulation 2005;111:3158-3166.
ABSTRACT
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Cost-Utility Analyses in Orthopaedic Surgery
Brauer et al.
JBJS 2005;87:1253-1259.
ABSTRACT
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Risk Perception, Risk Communication, and Stakeholder Involvement for Biosolids Management and Research
Beecher et al.
J. Environ. Qual. 2005;34:122-128.
ABSTRACT
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Inclusion of cost effectiveness in licensing requirements of new drugs: the fourth hurdle
Taylor et al.
BMJ 2004;329:972-975.
FULL TEXT
Cost effectiveness of foldable multifocal intraocular lenses compared to foldable monofocal intraocular lenses for cataract surgery
Dolders et al.
Br J Ophthalmol 2004;88:1163-1168.
ABSTRACT
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Inside Information: Financial Conflicts of Interest for Research Subjects in Early Phase Clinical Trials
Helft et al.
JNCI J Natl Cancer Inst 2004;96:656-661.
ABSTRACT
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Inside the Triple Helix: Technology Transfer And Commercialization In The Life Sciences
Campbell et al.
Health Aff (Millwood) 2004;23:64-76.
ABSTRACT
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Quantitative analysis of sponsorship bias in economic studies of antidepressants
Baker et al.
Br. J. Psychiatry 2003;183:498-506.
ABSTRACT
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Brains, claims, and the pharmaceutical industry
Alberts et al.
BMJ 2003;327:E107-109.
FULL TEXT
Industry-Sponsored Economic Studies in Critical and Intensive Care Versus Studies Sponsored by Nonprofit Organizations
Hartmann et al.
J Intensive Care Med 2003;18:265-268.
ABSTRACT
Association of Funding and Conclusions in Randomized Drug Trials: A Reflection of Treatment Effect or Adverse Events?
Als-Nielsen et al.
JAMA 2003;290:921-928.
ABSTRACT
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Industry Funding of Clinical Trials: Benefit or Bias?
Chopra
JAMA 2003;290:113-114.
FULL TEXT
Pharmaceutical industry sponsorship and research outcome and quality: systematic review
Lexchin et al.
BMJ 2003;326:1167-1170.
ABSTRACT
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Getting it right: industry sponsorship and medical research
Baird
CMAJ 2003;168:1267-1269.
FULL TEXT
Conflicts of Interest and AJRCCM: Restating Policy and a New Form to Upload
Tobin
Am. J. Respir. Crit. Care Med. 2003;167:1161-1164.
FULL TEXT
Authors' Financial Relationships With the Food and Beverage Industry and Their Published Positions on the Fat Substitute Olestra
Levine et al.
AJPH 2003;93:664-669.
ABSTRACT
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Restoring Balance to Industry-Academia Relationships in an Era of Institutional Financial Conflicts of Interest: Promoting Research While Maintaining Trust
Johns et al.
JAMA 2003;289:741-746.
ABSTRACT
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Scope and Impact of Financial Conflicts of Interest in Biomedical Research: A Systematic Review
Bekelman et al.
JAMA 2003;289:454-465.
ABSTRACT
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The Thought Style of Physicians: Strategies for Keeping up with Medical Knowledge
de Camargo
Social Studies of Science 2002;32:827-855.
ABSTRACT
Economic Evaluations of Immunoprophylaxis in Infants at High Risk for Respiratory Syncytial Virus: Shedding Light or Creating Confusion?
Klassen
Arch Pediatr Adolesc Med 2002;156:1180-1181.
FULL TEXT
Efficacy, safety, and cost of new anticancer drugs
Calvert et al.
BMJ 2002;325:1302-1302.
FULL TEXT
Economic Analyses of Respiratory Syncytial Virus Immunoprophylaxis in High-Risk Infants: A Systematic Review
Kamal-Bahl et al.
Arch Pediatr Adolesc Med 2002;156:1034-1041.
ABSTRACT
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Financial Conflicts of Interest in Human Subjects Research: The Problem of Institutional Conflicts
Barnes and Florencio
J Law Med Ethics 2002;30:390-402.
Efficacy, safety, and cost of new anticancer drugs
Garattini and Bertele'
BMJ 2002;325:269-271.
FULL TEXT
Conflicts of Interest in Clinical Research: Addressing the Issue of Physician Remuneration
Caulfield and Griener
J Law Med Ethics 2002;30:305-308.
Alteplase for stroke: money and optimistic claims buttress the "brain attack" campaign * Commentary: Who pays the guideline writers? * Commentary: Thrombolysis in stroke: it works!
Lenzer et al.
BMJ 2002;324:723-729.
FULL TEXT
Physician-Industry Relations. Part 1: Individual Physicians
Coyle and for the Ethics and Human Rights Committee, America
ANN INTERN MED 2002;136:396-402.
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Does a drug do better when it is new?
Fossati et al.
Ann Oncol 2002;13:470-473.
ABSTRACT
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Economic Analysis of Vinorelbine Plus Cisplatin Versus Paclitaxel Plus Carboplatin for Advanced Non-Small-Cell Lung Cancer
Ramsey et al.
JNCI J Natl Cancer Inst 2002;94:291-297.
ABSTRACT
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Relationships Between Authors of Clinical Practice Guidelines and the Pharmaceutical Industry
Choudhry et al.
JAMA 2002;287:612-617.
ABSTRACT
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The association between funding by commercial interests and study outcome in randomized controlled drug trials
Yaphe et al.
Fam Pract 2001;18:565-568.
ABSTRACT
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Dancing with the porcupine: rules for governing the university-industry relationship
Lewis et al.
CMAJ 2001;165:783-785.
FULL TEXT
In Search of the Magic Nutraceutical: Problems with Current Approaches
Heyland
J. Nutr. 2001;131:2591S-2595.
ABSTRACT
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Time for Introspection
Varkey
Chest 2001;119:1255-1256.
FULL TEXT
Role of Perspective and Other Uncertainties in Cost-Effectiveness Assessments in Advanced Prostate Cancer
Hillner and Roberts
JNCI J Natl Cancer Inst 2000;92:1704-1706.
FULL TEXT
Assessing Faculty Financial Relationships With Industry: A Case Study
Boyd and Bero
JAMA 2000;284:2209-2214.
ABSTRACT
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Conflict of Interest and the Public Trust
DeAngelis
JAMA 2000;284:2237-2238.
FULL TEXT
Systematic Overview of Cost-Utility Assessments in Oncology
Earle et al.
JCO 2000;18:3302-3317.
ABSTRACT
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Efficacy of Glucosamine and Chondroitin for Treatment of Osteoarthritis
Mautone et al.
JAMA 2000;284:1241-1241.
FULL TEXT
Uneasy Alliance -- Clinical Investigators and the Pharmaceutical Industry
Bodenheimer
NEJM 2000;342:1539-1544.
FULL TEXT
The Plight of Academic Health Centers
DeAngelis
JAMA 2000;283:2438-2439.
FULL TEXT
Problems With the Interpretation of Pharmacoeconomic Analyses: A Review of Submissions to the Australian Pharmaceutical Benefits Scheme
Hill et al.
JAMA 2000;283:2116-2121.
ABSTRACT
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Pharmacoeconomic Analyses: Making Them Transparent, Making Them Credible
Rennie and Luft
JAMA 2000;283:2158-2160.
FULL TEXT
Sources of Bias in the Economic Analysis of New Drugs
Gagnon et al.
JAMA 2000;283:1423-1424.
FULL TEXT
Conflict of Interest and Cost-effectiveness Analysis
Krimsky
JAMA 1999;282:1474-1475.
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