Context Increasing contact has been reported between physicians and the pharmaceutical
industry, although no data exist in the literature regarding potential financial
conflicts of interest for authors of clinical practice guidelines (CPGs).
These interactions may be particularly relevant since CPGs are designed to
influence the practice of a large number of physicians.
Objective To quantify the extent and nature of interactions between authors of
CPGs and the pharmaceutical industry.
Design, Setting, and Participants Cross-sectional survey of 192 authors of 44 CPGs endorsed by North American
and European societies on common adult diseases published between 1991 and
July 1999. One hundred authors (52%) provided usable responses representing
37 of 44 different CPGs that we identified.
Main Outcome Measures Nature and extent of interactions of authors with drug manufacturers;
disclosure of relationships in published guidelines; prior discussion among
authors regarding relationships; beliefs regarding whether authors' own relationships
or those of their colleagues influenced treatment recommendations in guidelines.
Results Eighty-seven percent of authors had some form of interaction with the
pharmaceutical industry. Fifty-eight percent had received financial support
to perform research and 38% had served as employees or consultants for a pharmaceutical
company. On average, CPG authors interacted with 10.5 different companies.
Overall, an average of 81% (95% confidence interval, 70%-92%) of authors per
CPG had interactions. Similarly, all of the CPGs for 7 of the 10 diseases
included in our study had at least 1 author who had some interaction. Fifty-nine
percent had relationships with companies whose drugs were considered in the
guideline they authored, and of these authors, 96% had relationships that
predated the guideline creation process. Fifty-five percent of respondents
indicated that the guideline process with which they were involved had no
formal process for declaring these relationships. In published versions of
the CPGs, specific declarations regarding the personal financial interactions
of individual authors with the pharmaceutical industry were made in only 2
cases. Seven percent thought that their own relationships with the pharmaceutical
industry influenced the recommendations and 19% thought that their coauthors'
recommendations were influenced by their relationships.
Conclusions Although the response rate for this survey was low, there appears to
be considerable interaction between CPG authors and the pharmaceutical industry.
Our study highlights the need for appropriate disclosure of financial conflicts
of interest for authors of CPGs and a formal process for discussing these
conflicts prior to CPG development.
Interactions between physicians and the pharmaceutical industry have
received increasing amounts of attention over the last several years. Several
authors have described significant contact between the pharmaceutical industry
and academic researchers,1 faculty physicians,2 community physicians,3
residents,4 and medical students.5
More importantly, these types of interactions have been shown to influence
prescribing patterns,6 stimulate requests for
addition of drugs to hospital formularies,2
result in favorable publications7 and research
articles,8,9 and be related to
the lack of publication of unfavorable articles.10
Clinical practice guidelines (CPGs) are intended to present a synthesis
of current evidence and recommendations preformed by expert clinicians and
may affect the practice of large numbers of physicians. As a result, any influence
that the authors of CPGs experience from their interactions with pharmaceutical
companies may be transmitted many times over to the readers of CPGs. Consequently,
if individual authors have relationships that pose a potential conflict of
interest, readers of these CPGs may wish to know about them to evaluate the
merit of those guidelines.
To date, no published data exists regarding the extent to which the
authors of CPGs interact with the pharmaceutical industry. This study seeks
to provide empirical evidence concerning this issue to improve the process
of CPG development in the future.
We attempted to compare the amount of financial interaction that authors
of CPGs had with the pharmaceutical industry with the amount of interaction
that was disclosed in the published guidelines that they had authored. We
also sought to assess the nature of these interactions and the authors' perceptions
of the impact of interactions on recommendations made by the guideline committee.
We asked 4 specific questions: (1) How much interaction do authors of clinical
practice guidelines have with drug manufacturers and what is the nature of
this interaction (ie, do the relationships predate or postdate the guideline
writing process)? (2) What physician-pharmaceutical interactions are disclosed
in the published guidelines? (3) Prior to beginning the guideline creation
process, was there any discussion among the guideline authors regarding relationships
with the pharmaceutical industry? and (4) Do guideline authors believe that
their relationships or those of their colleagues influence the treatment recommendations
that were put forth in the guidelines?
Selection and Review of Articles
Authors were identified by reviewing CPGs endorsed by North American
and European societies on common adult diseases published between 1991 and
July 1999. The list of medical conditions to be included was created using
the 20 most commonly prescribed drugs that are paid for by the Ontario Drug
Benefit Program. Drugs that are used symptomatically to treat many potentially
nonspecific conditions were excluded (eg, acetaminophen with codeine, lorazepam).
If not already included, we added conditions that accounted for the 5 most
common admission diagnoses to the internal medicine services at our hospitals
(ie, pneumonia, congestive heart failure, coronary artery disease, chronic
obstructive pulmonary disease/asthma, and gastrointestinal bleeding). Finally,
we excluded diseases for which CPGs did not exist.
Pertinent CPGs were identified through the MEDLINE database, reference
lists from published articles, and interviews with expert clinicians. We restricted
our sample to CPGs that had been endorsed by a recognized North American or
European society and had identifiable authors. We selected the principal authors
and, when indicated, those who participated in drafting the guideline to be
surveyed.
The CPGs were reviewed and specific declarations of potential financial
conflict of interest were recorded. Declarations regarding the guideline creation
process and individual authors were classified as no specific declaration
made, declaration that no financial interaction existed, declaration that
funding was received from a pharmaceutical company, or declaration that funding
was received from a nonindustry source (eg, government agency, professional
society/association). Statements indicating that the guidelines had been prepared
or approved by the endorsing professional association without explicitly indicating
from where funds had been received were coded as having no specific declaration
made.
Survey Instrument and Data Collection
Two surveys were used in this study. First, a survey instrument based
on that of Chren and Landefeld2 and used by
Stelfox et al7 was developed to examine authors'
financial interactions with pharmaceutical companies. Manufacturers of drugs
used to manage diabetes, chronic obstructive pulmonary disease/asthma, hypertension,
pneumonia, coronary artery disease, congestive heart failure, hyperlipidemia,
osteoarthritis, depression, and peptic ulcer disease were identified. For
each of these manufacturers, authors were asked whether they had any of 6
types of financial interactions, including support for attendance at a symposium
(eg, funds for travel expenses), honorarium for speaking at a symposium, support
for organization of an educational program, support for research, employment
by or consultancy for the company, and equity in the company.
The addresses of the corresponding authors were obtained from the articles,
a citation index, and other articles published by the same authors. All authors
were mailed the survey questionnaire with a cover letter explaining the purpose
of the study. Reminder letters and questionnaires were mailed to authors who
did not respond to the first mailing within 12 weeks.
Second, respondents to the first survey were resurveyed to characterize
the nature of relationships and the disclosure process. Authors were asked
whether their relationships specifically involved companies whose drugs were
considered or included in the guideline they authored, whether these relationships
predated or postdated the guideline process, whether they believed their own
relationships or those of their coparticipants influenced the recommendations
that were put forward, whether there was discussion among the participants
prior to beginning the guideline process regarding any relationships and whether
this process was formalized, and how potential conflicts of interest were
managed.
Descriptive statistics were used to examine the results of both quantitative
surveys. The results are reported as proportions and means with 95% confidence
intervals (CIs). The rate of response to the surveys was similarly analyzed.
Analyses were conducted using STATA, version 7 (STATA Corp, College Station,
Tex).
One hundred twenty CPGs were identified by our search strategy, of which
35 were excluded because a major North American or European society did not
endorse the CPG and 38 were excluded because they were editorials about CPGs
or comparisons of different CPGs. Therefore, 47 CPGs were initially included.11-57
Subsequently, 1 CPG was excluded because the authors could not be identified55 and 2 CPGs were excluded after the authors had been
surveyed since these were evaluations of CPGs rather than actual CPGs.56,57 Therefore, 44 CPGs with 192 authors
were included in the study.
Current addresses of 13 authors could not be located and 3 authors had
died, resulting in a total of 176 potentially contactable authors. Of these,
107 authors (61%) responded representing 37 of the 44 CPGs included in our
study. Therefore, 7 guidelines were not represented in our final sample.11,24,32,39,40,42,54
Despite this, all of the disease states that were initially included in our
study protocol were still represented by at least 2 CPGs, with the exception
of depression, for which there was only 1 CPG included in the sample and for
which we received a response. Seven respondents refused to participate, all
of whom were involved with different guidelines. Three of these 7 authors
were from Europe, 2 were from the United States, and 2 were from Canada. This
left 100 completed surveys, which form the basis of our results. Overall,
the response rate was 57% of potentially contactable authors and 52% of all
authors initially included in our sample. The distribution of sex and disease
to which the guidelines pertained was similar for respondents and nonrespondents;
however, the distribution of current country of residence was not. Sixty-three
percent of authors currently residing in the United States did not respond
whereas 29% of authors living in Canada did not respond (P = .001).
Twenty-eight (26%) of 107 authors responded with a letter attached to
their survey. These letters could be interpreted as being supportive (21%),
neutral (57%), or critical (21%) of our study.
Of the 100 authors who completed the first survey, 1 had died and 1
had moved and was unreachable, leaving 98 potentially contactable authors
for the second survey. Of these, 82 (83%) responded. One of these authors
refused to participate and 1 could not recall the nature of the disclosure
process and, therefore, left the survey blank. Consequently, the response
rate for the second survey was 82%.
CPG Author-Pharmaceutical Manufacturer Interactions
The nature of the authors' relationships with pharmaceutical companies
is shown in Table 1. Eighty-seven
percent of the responding authors had some form of interaction with the pharmaceutical
industry. Fifty-eight percent had received financial support to perform research
and 38% had served as employees or consultants for a pharmaceutical company.
The mean number of companies with which authors who did have financial
relationships interacted is shown in Table
1. On average, CPG authors interacted with 10.5 different companies.
Authors who received support for research received this funding from a mean
of 6.7 companies and those who served as employees or consultants for pharmaceutical
companies did so for a mean of 5.7 companies.
Table 2 shows response rates
and interactions categorized by the diseases to which the CPGs included in
our sample pertained. All of the CPGs for 7 of the 10 disease states had at
least 1 author who had some level of interaction. Similarly, the average percentage
of authors per CPG who had interactions was 100% for 6 of the 10 disease states.
Overall, an average of 81% (95% CI, 70%-92%) of authors per guideline had
interactions with the pharmaceutical industry.
Fifty-nine percent of authors had relationships with companies whose
products were specifically considered or included in the guideline they authored
(Table 3). Of these, 96% and 53%
had relationships that predated and postdated the guideline process, respectively.
Only 7% believed that their own relationships influenced the treatment
recommendations (Table 3). Nineteen
percent believed that their coauthors' recommendations were influenced by
relationships with the pharmaceutical industry.
Guideline Conflict of Interest Declarations
Forty-five percent of authors reported that prior to beginning the guideline
process, discussion occurred among the guideline authors regarding their relationships
with the pharmaceutical industry. Of these, 61% reported that there was a
formal process for this discussion and 75% indicated that all members of the
guideline committee participated.
In the published versions of the 44 CPGs included in the study, authors
declared that they had personal financial interactions with the pharmaceutical
industry in only 1 guideline51 (Table 4). Similarly, only 1 guideline declared that the authors
had no conflicts of interest.15 In the majority
of cases (42 of 44 guidelines), no declarations were made with respect to
the authors' potential conflicts of interest.
In 11 of the 44 CPGs, a declaration was made that a pharmaceutical company
had sponsored the guideline creation and writing process.14,16,21-24,27,32,43,46,47
Nonindustry organizations sponsored 9 CPGs.15,17,18,21,27,30,40,41,51
Two of these guidelines were supported by both industry and governmental sources.21,27
Although the results of this study must be interpreted cautiously in
light of the relatively low response rate, our results appear to indicate
that most CPG authors have interactions with pharmaceutical companies and
that a significant proportion work as employees/consultants for drug manufacturers.
Moreover, a majority of our respondents indicated that they had relationships
with companies whose products were considered in the guideline that they authored,
and of these, almost all had relationships that predated the guideline creation
process.
The majority of responding authors believed that their relationships
had no influence on the recommendations that they put forward. Ideally, we
would have liked to have objectively assessed whether this was true by evaluating
whether guidelines authored by individuals with relationships recommended
use of different therapies than those guidelines authored by individuals without
relationships. Unfortunately, most authors had relationships and virtually
all guidelines permitted use of a wide range of drugs as first-line agents
"if clinically indicated," thereby making any differentiation impossible.
Nevertheless, the authors' perceptions of the influence of their relationships
are in stark contrast with the large body of literature that indicates that
these types of relationships are indeed significant in other domains.2-10
Moreover, almost 20% of the respondents believed that their colleagues' relationships
influenced the recommendations that they put forward.
We wonder whether academicians and physicians underestimate the impact
of relationships on their actions because the nature of their professions
is the pursuit of objective unbiased information. Unfortunately, bias may
occur both consciously and subconsciously, and therefore, its influence may
go unrecognized. In fact, pharmaceutical marketing or "detailing" may rely
on the impact of these more subtle forms of influence.58
Concern about bias in interpretation of outcomes in randomized trials led
to the practice of blinding subjects, their caregivers, and outcome assessors
to the knowledge of which treatment the subject received. Is the situation
regarding CPG authorship not analogous?
Unlike relationships that individual authors or physicians have with
the pharmaceutical industry, financial conflicts of interest for authors of
CPGs are of particular importance since they may not only influence the specific
practice of these authors but also those of the physicians following the recommendations
contained within the guidelines.
There are several possible explanations for our low response rate. First,
physicians' interactions with the pharmaceutical industry have received increasing
amounts of attention in the medical literature1-10
and popular press. As a consequence, physicians may have been reluctant to
disclose their relationships. Second, the cover letter that we sent to our
survey participants made no promise of anonymity. Rather, we indicated that
participation in our survey was voluntary. Although we have presented our
results in aggregate and never intended to identify individual physicians,
it is possible that some authors may have been concerned about being recognized
and therefore preferred to not respond. Therefore, based on these factors,
it is possible that nonrespondents actually had a higher degree of interaction
with the pharmaceutical industry than respondents. Consequently, our low response
rate may have actually biased our results by underestimating the already high
degree of interaction that we observed.
To put our results in perspective without unduly biasing our respondents,
we conducted semistructured interviews with 5 guideline authors after the
second survey had been completed. These authors underscored the lack of formal
process for CPG authors to declare potential conflicts of interest and to
sensitize each other to subtle or subconscious influences, especially for
CPGs that were authored more than 5 years ago. In contrast, the interviewees
thought that it may be neither possible nor desirable to exclude authors who
are involved with industry since the "experts" who write guidelines are the
same individuals who are most likely to receive financial support to conduct
research. Moreover, our interviewees suggested that an author's objectivity
might actually be maintained by having multiple small relationships with different
pharmaceutical companies as opposed to large relationships with a few companies.
The authors also suggested that relationships with pharmaceutical industries
are not the only type of potential conflicts of interest that exist. Concerns
regarding obtaining continued funding from governmental agencies (eg, by ensuring
that one's government-funded research is included in the studies cited by
a CPG) or of individual academic promotion (eg, by ensuring that one's own
research is included in the studies cited by a CPG) may also influence the
guideline process and may serve as forms of "dual commitment."
Based on our results and the considerable debate that has taken place
about the relationships between clinical researchers and the pharmaceutical
industry, we propose the following recommendations for the management of potential
financial conflicts of interest for authors of clinical practice guidelines.
First, the process whereby authors disclose their potential conflicts
of interest must be made more formal. In particular, authors must disclose
relationships with the pharmaceutical industry before guideline meetings are
held. A full discussion must occur among the participants before the start
of the writing process about each person's relationships and how significant
relationships (eg, those that predate the guideline process, involve large
sums of money, or involve equity positions in companies) will be managed.
Participants should be sensitive to the possibility that the influence of
these relationships may subconsciously affect their judgments.
Second, authors who have relationships with the pharmaceutical industry
need not necessarily be excluded from participating in the guideline creation
process. However, authors with significant conflicts of interest should likely
be excluded. What level of conflict is significant is clearly a contentious
issue. Is there a threshold below which authors will not perceive subconscious
influences from their relationships with pharmaceutical companies? The only
threshold that is not arbitrary is zero, implying that all authors with any
relationships would be excluded. This standard, however, is both impractical
and likely too strict. Thus, groups will have to decide on this issue for
themselves. However, we do think that authors who hold equity in a company
whose products are being considered in the guideline process should be disqualified.
This is consistent with the current practices of most governmental granting
agencies in North America and the editorial policies of most major medical
journals.
Third, there must be complete disclosure to the readers of CPGs of individual
authors' financial relationships with the pharmaceutical industry. Ideally,
this should occur in the printed version of the guideline. However, if this
is not feasible given the large number of authors who may participate in a
CPG and practical limitations on space, alternative forms of disclosure, such
as the journal's Web site, could be used.
In conclusion, there appears to be a high degree of interaction between
authors of clinical practice guidelines and the pharmaceutical industry. These
specific interactions may influence the practice of a very large number of
physicians. We believe that our study highlights the need for appropriate
disclosure of financial conflicts of interest for authors of CPGs and a formal
process for discussing these conflicts prior to CPG development.
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