Conflict of Interest Reporting by Authors Involved in Promotion of Off-Label Drug Use: An Analysis of Journal Disclosures

Background

Litigation documents reveal that pharmaceutical companies have paid physicians to promote off-label uses of their products through a number of different avenues. It is unknown whether physicians and scientists who have such conflicts of interest adequately disclose such relationships in the scientific publications they author.

Methods and Findings

We collected whistleblower complaints alleging illegal off-label marketing from the US Department of Justice and other publicly available sources (date range: 1996–2010). We identified physicians and scientists described in the complaints as having financial relationships with defendant manufacturers, then searched Medline for articles they authored in the subsequent three years. We assessed disclosures made in articles related to the off-label use in question, determined the frequency of adequate disclosure statements, and analyzed characteristics of the authors (specialty, author position) and articles (type, connection to off-label use, journal impact factor, citation count/year). We identified 39 conflicted individuals in whistleblower complaints. They published 404 articles related to the drugs at issue in the whistleblower complaints, only 62 (15%) of which contained an adequate disclosure statement. Most articles had no disclosure (43%) or did not mention the pharmaceutical company (40%). Adequate disclosure rates varied significantly by article type, with commentaries less likely to have adequate disclosure compared to articles reporting original studies or trials (adjusted odds ratio [OR] = 0.10, 95%CI = 0.02–0.67, p = 0.02). Over half of the authors (22/39, 56%) made no adequate disclosures in their articles. However, four of six authors with ≥25 articles disclosed in about one-third of articles (range: 10/36–8/25 [28%–32%]).

Conclusions

One in seven authors identified in whistleblower complaints as involved in off-label marketing activities adequately disclosed their conflict of interest in subsequent journal publications. This is a much lower rate of adequate disclosure than has been identified in previous studies. The non-disclosure patterns suggest shortcomings with authors and the rigor of journal practices. Please see later in the article for the Editors'' Summary     

Conflicts of Interest among Authors of Clinical Practice Guidelines for Glycemic Control in Type 2 Diabetes Mellitus

Background

Conflict of interest (COI) is an important potential source of bias in the development of clinical practice guidelines (CPGs).

Objectives

To examine rates of disclosure of COI, including financial interests in companies that manufacture drugs that are recommended in CPGs on glycemic control in type 2 diabetes mellitus, and to explore the relationship between recommendations for specific drugs in a guideline and author COI.

Methods

We identified a cohort of relevant guidelines from the National Guideline Clearinghouse (NGC) and abstracted COI disclosures from all guideline authors for this observational, cross-sectional study. We determined which hypoglycemic drugs were recommended in each guideline, and explored the relationship between specific disclosures and whether a drug was recommended.

Results

Among 13 included guidelines, the percentage of authors with one or more financial disclosures varied from 0 to 94% (mean 44.2%), and was particularly high for two US-based guidelines (91% and 94%). Three guidelines disclosed no author financial COI. The percentage of authors with disclosures of financial interests in manufacturers of recommended drugs was also high (mean 30%). On average, 56% of manufacturers of patented drugs recommended in each guideline had one or more authors with a financial interest in their company. We did not find a significant relationship between financial interests and whether a drug was recommended in our sample; US-based guidelines were more likely to make recommendations for a specific drug compared to non-US based guidelines.

Discussion

Authors of this cohort of guidelines have financial interests directly related to the drugs that they are recommending. Although we did not find an association between author COI and drugs recommended in these guidelines and we cannot draw conclusions about the validity of the recommendations, the credibility of many of these guidelines is in doubt.     

Reporting science and conflicts of interest in the lay press

Background

Forthright reporting of financial ties and conflicts of interest of researchers is associated with public trust in and esteem for the scientific enterprise.

Methods/Principal Findings

We searched Lexis/Nexis Academic News for the top news stories in science published in 2004 and 2005. We conducted a content analysis of 1152 newspaper stories. Funders of the research were identified in 38% of stories, financial ties of the researchers were reported in 11% of stories, and 5% reported financial ties of sources quoted. Of 73 stories not reporting on financial ties, 27% had financial ties publicly disclosed in scholarly journals.

Conclusions/Significance

Because science journalists often did not report conflict of interest information, adherence to gold-standard recommendations for science journalism was low. Journalists work under many different constraints, but nonetheless news reports of scientific research were incomplete, potentially eroding public trust in science.     

Conflict of Interest Disclosures for Clinical Practice Guidelines in the National Guideline Clearinghouse

Background

Conflict of interest (COI) is an important potential source of bias in the development of clinical practice guidelines (CPGs) and high rates of COI among guideline authors have been reported in the past. Our objective was to report current rates of disclosure and specific author COI across a broad range of CPGs and to examine whether CPG characteristics were associated with the presence of disclosures and of conflicts.

Methods and Findings

We selected a random sample of 250 CPGs listed in the National Guideline Clearinghouse on November 22, 2010, representing approximately a 10% sample of guidelines listed in the NGC on that date. We abstracted information on author COI from each CPG and examined predictors of the disclosures and COI using a logistic generalized estimating equation regression model. 87% of organizations developing guidelines had a CPG-specific policy, however, 40% of CPGs did not indicate that they had collected disclosures from guideline authors. In addition, 42% of organizations that did collect author disclosures did not have those disclosures available in the public domain. Of CPGs where we had disclosures for all authors, 60% had one or more authors with a conflict. On average, 28% of the authors of CPGs with available disclosures had a COI. Guidelines that were published in journals with an impact factor greater than 5.0 were more likely to have one or more authors with a COI than guidelines not published in journals.

Conclusions

Rates of disclosure of author COI and the public availability of that information are unacceptably low, however rates of COI among guideline authors may have decreased in recent years. Continued efforts are needed to establish and enforce optimal COI policies in clinical practice guideline development in order to minimize the risk of bias associated with those conflicts.     

HIV status disclosure and retention in care in HIV-infected adolescents on antiretroviral therapy (ART) in West Africa

Objective

We assessed the effect of HIV status disclosure on retention in care from initiation of antiretroviral therapy (ART) among HIV-infected children aged 10 years or more in Cote d''Ivoire, Mali and Sénégal.

Methods

Multi-centre cohort study within five paediatric clinics participating in the IeDEA West Africa collaboration. HIV-infected patients were included in this study if they met the following inclusion criteria: aged 10–21 years while on ART; having initiated ART≥200 days before the closure date of the clinic database; followed ≥15 days from ART initiation in clinics with ≥10 adolescents enrolled. Routine follow-up data were merged with those collected through a standardized ad hoc questionnaire on awareness of HIV status. Probability of retention (no death or loss-to-follow-up) was estimated with Kaplan-Meier method. Cox proportional hazard model with date of ART initiation as origin and a delayed entry at date of 10th birthday was used to identify factors associated with death or loss-to-follow-up.

Results

650 adolescents were available for this analysis. Characteristics at ART initiation were: median age of 10.4 years; median CD4 count of 224 cells/mm³ (47% with severe immunosuppression), 48% CDC stage C/WHO stage 3/4. The median follow-up on ART after the age of 10 was 23.3 months; 187 adolescents (28.8%) knew their HIV status. The overall probability of retention at 36 months after ART initiation was 74.6% (95% confidence interval [CI]: 70.5–79.0) and was higher for those disclosed compared to those not: adjusted hazard ratio for the risk of being death or loss-to-follow-up = 0.23 (95% CI: 0.13–0.39).

Conclusion

About 2/3 of HIV-infected adolescents on ART were not aware of their HIV status in these ART clinics in West Africa but disclosed HIV status improved retention in care. The disclosure process should be thus systematically encouraged and organized in adolescent populations.     

Promotional tone in reviews of menopausal hormone therapy after the Women's Health Initiative: an analysis of published articles

Background

Even after the Women''s Health Initiative (WHI) found that the risks of menopausal hormone therapy (hormone therapy) outweighed benefit for asymptomatic women, about half of gynecologists in the United States continued to believe that hormones benefited women''s health. The pharmaceutical industry has supported publication of articles in medical journals for marketing purposes. It is unknown whether author relationships with industry affect promotional tone in articles on hormone therapy. The goal of this study was to determine whether promotional tone could be identified in narrative review articles regarding menopausal hormone therapy and whether articles identified as promotional were more likely to have been authored by those with conflicts of interest with manufacturers of menopausal hormone therapy.

Methods and Findings

We analyzed tone in opinion pieces on hormone therapy published in the four years after the estrogen-progestin arm of the WHI was stopped. First, we identified the ten authors with four or more MEDLINE-indexed reviews, editorials, comments, or letters on hormone replacement therapy or menopausal hormone therapy published between July 2002 and June 2006. Next, we conducted an additional search using the names of these authors to identify other relevant articles. Finally, after author names and affiliations were removed, 50 articles were evaluated by three readers for scientific accuracy and for tone. Scientific accuracy was assessed based on whether or not the findings of the WHI were accurately reported using two criteria: (1) Acknowledgment or lack of denial of the risk of breast cancer diagnosis associated with hormone therapy, and (2) acknowledgment that hormone therapy did not benefit cardiovascular disease endpoints. Determination of promotional tone was based on the assessment by each reader of whether the article appeared to promote hormone therapy. Analysis of inter-rater consistency found moderate agreement for scientific accuracy (κ = 0.57) and substantial agreement for promotional tone (κ = 0.65). After discussion, readers found 86% of the articles to be scientifically accurate and 64% to be promotional in tone. Themes that were common in articles considered promotional included attacks on the methodology of the WHI, arguments that clinical trial results should not guide treatment for individuals, and arguments that observational studies are as good as or better than randomized clinical trials for guiding clinical decisions. The promotional articles we identified also implied that the risks associated with hormone therapy have been exaggerated and that the benefits of hormone therapy have been or will be proven. Of the ten authors studied, eight were found to have declared payment for speaking or consulting on behalf of menopausal hormone manufacturers or for research support (seven of these eight were speakers or consultants). Thirty of 32 articles (90%) evaluated as promoting hormone therapy were authored by those with potential financial conflicts of interest, compared to 11 of 18 articles (61%) by those without such conflicts (p = 0.0025). Articles promoting the use of menopausal hormone therapy were 2.41 times (95% confidence interval 1.49–4.93) as likely to have been authored by authors with conflicts of interest as by authors without conflicts of interest. In articles from three authors with conflicts of interest some of the same text was repeated word-for-word in different articles.

Conclusion

There may be a connection between receiving industry funding for speaking, consulting, or research and the publication of promotional opinion pieces on menopausal hormone therapy. Please see later in the article for the Editors'' Summary     

Addressing Women's Non-Maternal Healthcare Financing in Developing Countries: What Can We Learn from the Experiences of Rural Indian Women?

Background and Objectives

This paper focuses on the inadequate attention on women''s non-maternal healthcare in low- and middle-income countries. The study assessed the purchase of and financial access to non-maternal healthcare. It also scoped for mainstreaming household financial resources in this regard to suggest for alternatives.

Methods

A household survey through multi-stage stratified sampling in the state of Orissa interviewed rural women above 15 years who were neither pregnant nor had any pregnancy-related outcome six weeks preceding the survey. The questions explored on the processes, determinants and outcomes of health seeking for non-maternal ailments. The outcome measures were healthcare access, cost of care and financial access. The independent variables for bivariate and multivariate analyses were contextual factors, health seeking and financing pattern.

Results

The survey obtained a response rate of 98.64% and among 800 women, 43.8% had no schooling and 51% were above 60 years. Each woman reported at least one episode of non-maternal ailment; financial constraints prevented 68% from receiving timely and complete care. Distress coping measures (e.g. borrowings) dominated the financing source (67.9%) followed by community–based measures (32.1%). Only 6% had financial risk-protection; financial risk of not obtaining care doubled for women aged over 60 years (OR 2.00, 95% CI 0.84–4.80), seeking outpatient consultation (OR 2.01, 95% CI 0.89–4.81), facing unfavourable household response (OR 2.04, 95% CI 1.09–3.83), and lacking other financial alternatives (OR 2.13, 95% CI 1.11–4.07). When it comes to timely mobilization of funds and healthcare seeking, 90% (714) of the households preferred maternal care to non-maternal healthcare.

Conclusion

The existing financing options enable sub-optimal purchase of women''s non-maternal healthcare. Though dominant, household economy extends inadequate attention in this regard owing to its unfavourable approach towards non-maternal healthcare and limited financial capacity and support from other financial resources.     

Author self-citation in the general medicine literature

Background

Author self-citation contributes to the overall citation count of an article and the impact factor of the journal in which it appears. Little is known, however, about the extent of self-citation in the general clinical medicine literature. The objective of this study was to determine the extent and temporal pattern of author self-citation and the article characteristics associated with author self-citation.

Methodology/Principal Findings

We performed a retrospective cohort study of articles published in three high impact general medical journals (JAMA, Lancet, and New England Journal of Medicine) between October 1, 1999 and March 31, 2000. We retrieved the number and percentage of author self-citations received by the article since publication, as of June 2008, from the Scopus citation database. Several article characteristics were extracted by two blinded, independent reviewers for each article in the cohort and analyzed in multivariable linear regression analyses. Since publication, author self-citations accounted for 6.5% (95% confidence interval 6.3–6.7%) of all citations received by the 328 articles in our sample. Self-citation peaked in 2002, declining annually thereafter. Studies with more authors, in cardiovascular medicine or infectious disease, and with smaller sample size were associated with more author self-citations and higher percentage of author self-citation (all p≤0.01).

Conclusions/Significance

Approximately 1 in 15 citations of articles in high-profile general medicine journals are author self-citations. Self-citation peaks within about 2 years of publication and disproportionately affects impact factor. Studies most vulnerable to this effect are those with more authors, small sample size, and in cardiovascular medicine or infectious disease.     

Conflict of interest in clinical practice guideline development: a systematic review

Background

There is an emerging literature on the existence and effect of industry relationships on physician and researcher behavior. Much less is known, however, about the effects of these relationships and other conflicts of interest (COI) on clinical practice guideline (CPG) development and recommendations. We performed a systematic review of the prevalence of COI and its effect on CPG recommendations.

Methodology/Principal Findings

We searched Medline (1980 to March, 2011) for studies that examined the effect of COI on CPG development and/or recommendations. Data synthesis was qualitative. Twelve studies fulfilled inclusion criteria; 9 were conducted in the US. All studies reported on financial relationships of CPG authors with the pharmaceutical industry; 1 study also examined relationships with diagnostic testing and insurance companies. The majority of guidelines had authors with industry affiliations, including consultancies (authors with relationship, range 6–80%); research support (4–78%); equity/stock ownership (2–17%); or any COI (56–87%). Four studies reported multiple types of financial interactions for individual authors (number of types per author: range 2 to 10 or more). Data on the effect of COI on CPG recommendations were confined to case studies wherein authors with specific financial ties appeared to benefit from the related CPG recommendations. In a single study, few authors believed that their relationships influenced their recommendations. No studies reported on intellectual COI in CPGs.

Conclusions/Significance

There are limited data describing the high prevalence of COI among CPG authors, and only case studies of the effect of COI on CPG recommendations. Further research is needed to explore this potential source of bias.     

Factors associated with HIV/AIDS diagnostic disclosure to HIV infected children receiving HAART: a multi-center study in Addis Ababa, Ethiopia

Background

Diagnostic disclosure of HIV/AIDS to a child is becoming an increasingly common issue in clinical practice. Nevertheless, some parents and health care professionals are reluctant to inform children about their HIV infection status. The objective of this study was to identify the proportion of children who have knowledge of their serostatus and factors associated with disclosure in HIV-infected children receiving HAART in Addis Ababa, Ethiopia.

Methods

A cross-sectional study was conducted in five hospitals in Addis Ababa from February 18, 2008–April 28, 2008. The study populations were parents/caretakers and children living with HIV/AIDS who were receiving Highly Active Antiretroviral Therapy (HAART) in selected hospitals in Addis Ababa. Univariate and multivariate logistic regression analysis were carried out using SPSS 12.0.1 statistical software.

Results

A total of 390 children/caretaker pairs were included in the study. Two hundred forty three children (62.3%) were between 6–9 years of age. HIV/AIDS status was known by 68 (17.4%) children, 93 (29%) caretakers reported knowing the child''s serostatus two years prior to our survey, 180 (46.2%) respondents said that the child should be told about his/her HIV/AIDS status when he/she is older than 14 years of age. Children less than 9 years of age and those living with educated caregivers are less likely to know their results than their counterparts. Children referred from hospital''s in-patient ward before attending the HIV clinic and private clinic were more likely to know their results than those from community clinic.

Conclusion

The proportion of disclosure of HIV/AIDS diagnosis to HIV-infected children is low. Strengthening referral linkage and health education tailored to educated caregivers are recommended to increase the rate of disclosure.     

Room for improvement in conducting and reporting non-inferiority randomized controlled trials on drugs: a systematic review

Background

A non-inferiority (NI) trial is intended to show that the effect of a new treatment is not worse than the comparator. We conducted a review to identify how NI trials were conducted and reported, and whether the standard requirements from the guidelines were followed.

Methodology and Principal Findings

From 300 randomly selected articles on NI trials registered in PubMed at 5 February 2009, we included 227 NI articles that referred to 232 trials. We excluded studies on bioequivalence, trials on healthy volunteers, non-drug trials, and articles of which the full-text version could not be retrieved. A large proportion of trials (34.0%) did not use blinding. The NI margin was reported in 97.8% of the trials, but only 45.7% of the trials reported the method to determine the margin. Most of the trials used either intention to treat (ITT) (34.9%) or per-protocol (PP) analysis (19.4%), while 41.8% of the trials used both methods. Less than 10% of the trials included a placebo arm to confirm the efficacy of the new drug and active comparator against placebo, and less than 5.0% were reporting the similarity of the current trial with the previous comparator''s trials. In general, no difference was seen in the quality of reporting before and after the release of the CONSORT statement extension 2006 or between the high-impact and low-impact journals.

Conclusion

The conduct and reporting of NI trials can be improved, particularly in terms of maximizing the use of blinding, the use of both ITT and PP analysis, reporting the similarity with the previous comparator''s trials to guarantee a valid constancy assumption, and most importantly reporting the method to determine the NI margin.     

Conflict of interest in spine research reporting

Background

Medical studies are more likely to report favorable findings when a conflict of interest is declared. We aim to quantify and determine the effect of author disclosure of conflict of interest on scientific reporting.

Methods

Abstracts from an international spine research meeting (North American Spine Society 2010) were selected that specifically evaluated a device, biologic, or proprietary procedure. They were then made anonymous to reviewers. An item of interest was established in each of the abstracts in order to standardize evaluation. Next, three blinded reviewers independently rated the abstracts as favorable, neutral, or unfavorable with regard to the item of interest. Additionally, the blinded reviewers attempted to predict whether a related disclosure was made. The meeting disclosure index was used to tabulate the minimum US dollar value attributable to disclosures.

Results

Of the 344 total abstracts, 76 met inclusion criteria. In 79%, a related conflict of interest was reported. The amount of the disclosure was incompletely reported in 30% of cases. Where available, it averaged a cumulative minimum of $219,634 USD per abstract. The results of the abstracts were judged to be favorable, neutral, and unfavorable in 63%, 32% and 5% of abstracts, respectively. There was no correlation between the presence of a related disclosure and the findings of the studies (p = 0.81), although interpretation of this is limited by a small sample size and an overall apparent bias to report favorable studies. Additionally, the blinded reviewers were unable to predict whether a related disclosure was made (p = 0.40).

Conclusion

No association existed between the presence of a related disclosure and the results of the studies. While the actual compliance with reporting a potential conflict of interest is unable to be determined, the value amount related to the disclosures made was inadequately reported according to meeting guidelines.     

Epidemiologic behavior of obesity in the Maracaibo City metabolic syndrome prevalence study

Introduction

Obesity is a worldwide public health issue. Since the epidemiological behaviour of this disease is not well established in our country, the purpose of this study was to determinate its prevalence in the Maracaibo City, Zulia State- Venezuela.

Materials and Methods

A cross-sectional study was undertaken using the data set from the Maracaibo City Metabolic Syndrome Prevalence Study. The sample consists of 2108 individuals from both genders and randomly selected: 1119 (53.09%) women and 989 (46.91%) men. The participants were interrogated for a complete clinical history and anthropometric measurements. To classify obesity, the WHO criteria for Body Mass Index (BMI), and Waist Circumference (WC) from the IDF/NHLBI/AHA/WHF/IAS/IASO-2009 (IDF-2009) and ATPIII statements were applied.

Results

For BMI, obesity had an overall prevalence of 33.3% (n = 701), and according to gender women had 32.4% (n = 363) and men had 34.2% (n = 338). Overweight had a prevalence of 34.8% (n = 733), Normal weight had 29.8% (n = 629), and Underweight had 2.1% (n = 45). Adding Obesity and Overweight results, the prevalence of elevated BMI (>25 Kg/m²) was 68.1%. Using the IDF-2009 WC''s cut-off, Obesity had 74.2% prevalence, compared to 51.7% using the ATPIII parameters.

Conclusions

These results show a high prevalence of abdominal obesity in our locality defined by the WHO, IDF-2009 and ATPIII criteria, which were not designed for Latin-American populations. We suggest further investigation to estimate the proper values according to ethnicity, genetic background and sociocultural aspects.