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Friedberg M, Saffran B, Stinson TJ, Nelson W, Bennett CL. Evaluation of Conflict of Interest in Economic Analyses of New Drugs Used in Oncology. JAMA. 1999;282(15):1453–1457. doi:10.1001/jama.282.15.1453
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).
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
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
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.
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
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?
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
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
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
× 2 tables with an expected cell value less than 5) or Pearson χ2 tests. A 2-sided P value (against the null
hypothesis of no relationship between conclusion and funding source) less
than .05 was considered significant.
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
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
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
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
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
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