Pre-publication History Reporting of Conflicts of Interest in Guidelines of Preventive and Therapeutic Interventions Reporting of Conflicts of Interest in Practice Guidelines of Preventive and Therapeutic Interventions

Background. Guidelines published in major medical journals are very influential in


Background
Guidelines have assumed a major role in forming practitioner and patient decisions about appropriate health care [1]. It is important that such efforts are not affected by conflicts of interest and that guidelines are transparent to such potential conflicts. This is even more significant for clinical guidelines published in influential medical journals that are likely to have a major impact upon therapeutic and preventive clinical care and public health worldwide. However, there has been no study of the reporting of conflicts of interest in guidelines published in medical journals. We undertook an evaluation of this issue in a sample of publications of clinical guidelines.

Materials and Methods
Our study evaluated 6 prestigious medical journals that are likely to publish influential clinical guidelines. The journals were selected so as to include the 4 most extensively-cited clinical medicine interdisciplinary journals, as well as the most extensively-cited adult internal medicine journal and the most extensively-cited pediatric medicine journal according to the Institute of Scientific Information Journal Citation Report. Each selected journal received more than 20,000 citations in 1999. Thus we hand-searched the Annals of Internal Medicine, British Medical Journal (BMJ), Journal of the American Medical Association (JAMA), Lancet, New England Journal of Medicine and Pediatrics for guidelines published during 1979, 1984, 1989, 1994 and 1999. The appreciation of conflicts of interest has changed over the last 20 years and increasingly more strict policies have been adopted, especially in the 1990s. We aimed to evaluate whether this change is also reflected in a secular trend in the reporting of conflicts of interests in guideline publications. Therefore, we sampled guidelines across 5year intervals to cover a 20-year period. We preferred hand searching rather than computerized searches in an attempt to minimize loss of retrievals due to incomplete computerized coding. Two investigators independently hand-searched the pertinent volumes. Discrepancies were solved by a third investigator to reach consensus.
In order to reduce subjective interpretation of what constitutes a guideline publication we developed strict eligibility criteria. Eligible for the study were all articles that (I) contained in their titles, heading or abstracts (or introductory / summary paragraph when an abstract was missing) key words that were characteristic of guidelines ("guidelines" or "recommendations", "consensus [panelstatement-conference]", "clinical synthesis conference", "guidance", "policy statement", "practice parameter" and "position [paper-article-statement]"; and (II) had main focus on preventive and /or therapeutic interventions including health care delivery. We excluded papers where the main focus was on descriptive epidemiology, research design, diagnosis (diagnostic performance rather than clinical impact of diagnostic methods), risk assessment, legal issues, biology and/or pathophysiology. We specifically excluded editorials, commentaries, original randomized controlled trials, as well as systematic reviews and meta-analyses unless they were part of the guideline. Both full-length and shortened versions qualified, but comments and discussion items concerning guidelines were excluded. The last search for eligible guidelines was performed in mid-October 1999.
Data extraction, including journal, year, main subject focus, main country of origin, authorship, type(s) of interventions and funding, was performed on standardized forms. We also recorded whether conflicts of interest were mentioned at all, and if so, how much space was given for such disclosures. The amount of space given for conflict disclosure does not necessarily guarantee the completeness of disclosure or the quality of the conveyed information, but it can be used as a surrogate of the importance given to this information. This parameter has been previously used for other aspects of reporting in journal publications [2]. Finally, we recorded the nature of specific disclosed conflicts. We considered all reported conflicts of interest, financial and non-financial, that were judged to be relevant for publication by each journal. For each selected journal we examined the instructions to the authors over the last 20 years to examine if and when specific disclosure policies were available for conflicts of interest.
Using the Fisher's exact test we evaluated whether there were significant associations between characteristics of guidelines and the reporting of conflicts of interest. Analyses were conducted in SPSS 9.0 (SPSS Inc, Chicago, IL). P-values are two-tailed.

Results
We recovered 191 publications of eligible guidelines (table 1). All the 6 selected journals specifically state in their current instructions to the authors that potential conflicts of interest should be declared, and have implemented various conflict of interest policies. Guidelines have not been specifically excluded from conflict disclosure in any of the 6 journals. All 1999 and 1994 publications in these journals were subject to conflict disclosure policies. In addition, such policies existed also by 1989 for JAMA, Pediatrics and New England Journal of Medicine.
Only 7 guidelines (3.7%) disclosed potential conflicts of interest (table 1). The disclosure rate was 6.1% when estimated on the basis of the 115 guidelines published when specific disclosure policies were in place. All disclosures had been made in 1999 and for this year the disclosure percentage was 17.5% (7/40). Reporting was also related to specific journals (p=0.026), but the rate of disclosure was very low even in the journal with the highest disclosure rate (JAMA, 4/35 [11.4%]). The country of origin, focus (therapy, prevention or both), group authorship and emphasis on medication vs. other interventions were not related to reporting of conflicts of interest (p=1.00, 0.14, 1.00 and 1.00, respectively) suggesting the deficiency is universal. Guidelines funded mostly by the government, universities or major professional organizations almost never reported on potential conflicts of interest while guidelines funded by private or mixed sources were more likely to disclose potential conflicts (p < 0.001). Among guidelines where specific authors as-sumed primary responsibility for writing the manuscript, reporting of conflicts of interest was more common when there were more authors (p=0.004) (table 1).
Further analysis revealed that all guidelines reporting conflicts of interest dedicated less than 1/20 of a page for this reason and less than 1/100 of the total length of the article -with one exception where disclosure took 13 lines to report. In the entire database of 191 guidelines, a mere 18 authors disclosed a total of 24 potential conflicts of interest (table 2). The majority of the alluded items of conflict were for relatively minor issues (such as travel fees, speaker funds and consultation) while no author disclosed possessing stock in a company.
Sixty guidelines (27 of them published under explicit journal disclosure policies and 11 published in 1999) mentioned either specific authors or identified individuals within a panel who assumed responsibility for writing the manuscript. In total, 242 authors were listed in these guidelines (139 publishing under explicit journal disclosure policies and 79 in 1999 alone). Of those, only 15 authors disclosed conflicts of interest. The percentage of disclosing authors is 6.2% based on all years, 10.8% based on publications under explicit journal disclosure policies, and 19.0% based on 1999 alone. Panels of experts authored the other 131 guidelines, often with dozens of listed members or without detailed listing of contributors. In all these group-authored guidelines, only 3 members of one single panel disclosed conflicts of interest.

Discussion
Our study revealed that reporting of conflicts of interest in guidelines of healthcare interventions is probably largely neglected despite some recent improvement. Even in 1999, only 1 out of 6 clinical guidelines disclosed conflicts of interest. Reporting varied by journal. A recent study has shown that 50% of US medical journals with a circulation more than 1000 copies per issue (including, of course, all journals we searched in our study) have written policies regarding conflicts of interest [3,4].  Conflicts of interest may not be reported either because authors do not disclose them or because they are not published by the journals. Furthermore, cases of inconsistency between stated journal policy and practice have appeared in the recent literature [5].
It is estimated that the pharmaceutical industry in the United States spends $8000 to $13000 per year on each physician simply for marketing purposes [6,7] and this phenomenon is probably international [8]. It is unknown how these figures should be extrapolated to field experts who are authors of clinical guidelines. More studies are needed to examine the extent of financial and other connections of experts to the industry in their field of expertise. One study [9] found that 15% of lead authors from Massachusetts publishing in 14 major biomedical journals in 1992 had at least one major potential conflict of interest, such as serving on scientific advisory boards of biotechnology firms in their state; being officers, directors or major shareholders in biotechnology firms; or being listed as inventors in a relevant patent or patent application. In all, 34% of the sampled articles had at least one author with a financial conflict of interest directly relevant to the publication [9]. The proportion might have been larger if financial interest data could have been retrieved from additional out-of-state and international connections and if more non-financial conflicts of interest could have been captured as well. In another study of authors of 70 studies of calcium channel blockers for treating cardiovascular disorders [10], 96% of the authors of supportive studies had financial relationships with the manufacturers, as compared with 60% of neutral authors and 37% of critical authors. Only 2 of the 70 articles disclosed the authors' potential conflicts of interest. Finally, one study of faculty members at the University of California [11] found that 7.6% of investigators reported personal financial ties with sponsors of their research. Given the large heterogeneity in the policies of reporting faculty conflicts of interest [12,13], it is difficult to arrive at exact estimates of the frequency of serious competing interests in field experts.
In this study, it was not possible to determine exactly what might have been undisclosed, since the authors were sampled from all over the world and guidelines covered very diverse topics. Sorting out financial connections in a consistent fashion would have been practically impossible. Non-financial conflicts of interest would be even more intangible to the outsider. Nevertheless, one may speculate that competing interests may have been at least as common as what has been described in the other studies mentioned above. For example, the 1999 BMJ guideline about the management of hypertension [14] did not declare any competing interests. In a MEDLINE search, we were able to identify at least 66 randomized controlled trials of anti-hypertensive interventions authored by the guideline authors up to 1999 (range 1 to 34 per author). These trials evaluated a total of 27 different anti-hypertensive drugs (range 0 to 14 per author) in various doses and formulations and 9 other non-pharmaceutical interventions. In any case, funding of trials by the pharmaceutical industry does not mean that the investigators would be biased and it is expected that a panel of leading scientists would be able to balance on objective conclusions during the development of consensus. Still, it would have been useful to know what might have been the potential competing interests, including non-financial ones [15], of the panel members.
We found that conflicts of interest were rarely, if ever, published in clinical guideline reports funded by the government, universities or professional physician organizations. Although it may be anticipated that such sponsors may make more stringent efforts to assure objectivity in guideline development, it is still important that potential conflicts of interest of the individuals participating in the process should be acknowledged. This holds true even if group authorship is assumed. Conflicts of interest may be more worrisome when there is individual authorship. One would expect the objectivity of the guideline to be more vulnerable when only one or two individuals are authoring it. Nevertheless, the likelihood of disclosing conflicts of interest was smaller when few authors took responsibility for a guideline than when several authors were involved.
Recent studies have focused on deficiencies in the development and reporting of guidelines and have stressed the need to standardize the process [16,17,18]. Conflicts of interest can harm the credibility of guidelines. Competing interests may negatively influence the quality of clinical practice [19], as well as prescribing and professional behavior [6,8]. Even original studies [10] and cost-effectiveness analyses [20] may reach differing results depending on competing interests. Clinical guidelines are likely to be even more vulnerable to these influences.

Conclusions
Transparency, by means of disclosure of potential conflicts, could foster public trust. Such information would take minimal space to report and may help to obviate doubts regarding the integrity of clinical guidelines. Both guideline authors and journal editors should pay more attention to this important issue.

Competing interests
None declared