Conflicts of interest in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews: associations with recommendations.

BACKGROUND: Treatment and diagnostic recommendations are often made in clinical guidelines, reports from advisory committee meetings, opinion pieces such as editorials, and narrative reviews. Quite often, the authors or members of advisory committees have industry ties or particular specialty interests which may impact on which interventions are recommended. Similarly, clinical guidelines and narrative reviews may be funded by industry sources resulting in conflicts of interest. OBJECTIVES: To investigate to what degree financial and non-financial conflicts of interest are associated with favourable recommendations in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews. SEARCH METHODS: We searched PubMed, Embase, and the Cochrane Methodology Register for studies published up to February 2020. We also searched reference lists of included studies, Web of Science for studies citing the included studies, and grey literature sources. SELECTION CRITERIA: We included studies comparing the association between conflicts of interest and favourable recommendations of drugs or devices (e.g. recommending a particular drug) in clinical guidelines, advisory committee reports, opinion pieces, or narrative reviews. DATA COLLECTION AND ANALYSIS: Two review authors independently included studies, extracted data, and assessed risk of bias. When a meta-analysis was considered meaningful to synthesise our findings, we used random-effects models to estimate risk ratios (RRs) with 95% confidence intervals (CIs), with RR > 1 indicating that documents (e.g. clinical guidelines) with conflicts of interest more often had favourable recommendations. We analysed associations for financial and non-financial conflicts of interest separately, and analysed the four types of documents both separately (pre-planned analyses) and combined (post hoc analysis). MAIN RESULTS: We included 21 studies analysing 106 clinical guidelines, 1809 advisory committee reports, 340 opinion pieces, and 497 narrative reviews. We received unpublished data from 11 studies; eight full data sets and three summary data sets. Fifteen studies had a risk of confounding, as they compared documents that may differ in other aspects than conflicts of interest (e.g. documents on different drugs used for different populations). The associations between financial conflicts of interest and favourable recommendations were: clinical guidelines, RR: 1.26, 95% CI: 0.93 to 1.69 (four studies of 86 clinical guidelines); advisory committee reports, RR: 1.20, 95% CI: 0.99 to 1.45 (four studies of 629 advisory committee reports); opinion pieces, RR: 2.62, 95% CI: 0.91 to 7.55 (four studies of 284 opinion pieces); and narrative reviews, RR: 1.20, 95% CI: 0.97 to 1.49 (four studies of 457 narrative reviews). An analysis combining all four document types supported these findings (RR: 1.26, 95% CI: 1.09 to 1.44). One study investigating specialty interests found that the association between including radiologist guideline authors and recommending routine breast cancer screening was RR: 2.10, 95% CI: 0.92 to 4.77 (12 clinical guidelines). AUTHORS' CONCLUSIONS: We interpret our findings to indicate that financial conflicts of interest are associated with favourable recommendations of drugs and devices in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews. However, we also stress risk of confounding in the included studies and the statistical imprecision of individual analyses of each document type. It is not certain whether non-financial conflicts of interest impact on recommendations.

Antibiotics for recurrent acute pharyngo-tonsillitis: systematic review.

The purpose was to determine the current evidence for preferable antibiotic treatment in three common clinical situations with insufficient consensus: Q1: Can antibiotic treatment prevent future attacks of acute pharyngo-tonsillitis (APT) in patients with recurrent APT (RAPT)? Q2: Which antibiotic regimen is preferable in the treatment of APT in patients with RAPT? Q3: Which antibiotic regimen is preferable in the treatment of relapsing APT? Five databases were searched systematically for randomized clinical trials on patients with RAPT with or without current APT or with relapse of APT. Of the unique publications, 643 were found. Five studies addressing Q1 (n = 3) and Q2 (n = 2) met the eligibility criteria. No studies reporting on Q3 were included. Q1: Two studies found that clindamycin and cefpodoxime, respectively, were effective in preventing future APT episodes and in eradicating group A streptococci from the tonsils of RAPT patients. One study found that long-term azithromycin had no effect on the number of APT episodes. Q2: Two studies reported superior clinical and microbiological effects of clindamycin and amoxicillin with clavulanate, respectively, compared to penicillin. The four studies showing superior effects of clindamycin and amoxicillin with clavulanate were assessed to have high risk of bias. Hence, the level of evidence was moderate. There is considerable evidence to suggest that clindamycin and amoxicillin with clavulanate are superior to penicillin with preferable effects on the microbiological flora and the number of future attacks of APT in patients with RAPT. Antibiotic treatment is an option in patients with RAPT, who has contraindications for tonsillectomy.

Prevalence of various etiologies of hearing loss among cochlear implant recipients: Systematic review and meta-analysis.

OBJECTIVE: To investigate the etiology of deafness in cochlear implanted children and to address the question whether there is a need for more thorough diagnostics, especially concerning genetics. DESIGN: Systematic review. Four databases were searched for studies (year 2000-2014) on cochlear implanted children (n > 100). Studies were excluded if etiology had influenced their inclusion criteria. Eligibility and methodological quality were assessed independently by three authors. The studies' description of diagnostic evaluation was categorized in three groups. STUDY SAMPLE: Sixteen studies were included (5069 children). RESULTS: The most common etiological categories were 'Unknown' 40.3% (95% CI 32.8 to 48.0), 'Non-syndromic' 22.4% (95% CI 17.1 to 28.2), and 'Postnatal' 11.3% (95% CI 7.2 to 16.2). Studies published after 2006 had a lower proportion of 'Unknown' etiology 35.3% (95% CI 28.0 to 42.8) than older 45.5% (95% CI 31.0 to 60.4). Important information was missing from several studies: 11 (69%) studies did not provide detailed description on diagnostic evaluation of the etiology of deafness and had a higher proportion of 'Unknown' etiology. CONCLUSIONS: In order to ensure a higher level of comparability in future studies, we recommend agreement upon an international standard of diagnostics and the introduction of an international standard for reporting etiology.

International or national publication of case reports.

INTRODUCTION: Case reports are often regarded as second-class research, but are an important part of medical science as they often present first evidence of new discoveries. We here describe the type of case reports published in a Danish general medical journal. MATERIAL AND METHODS: We included all case reports published in Ugeskrift for Laeger in 2009. For each report, two authors extracted information on study characteristics and classified the relevance and the role of the report. RESULTS: We included 139 case reports written in Danish. Thirty-nine (28%) were of general relevance and 100 (72%) of speciality relevance. The median number of authors was three (range: 1-7). The first author was a non-specialist physician in 119 (86%) of the reports and the last author a specialist in 103 (78%). A total of 124 (89%) reports had an educational role, six (4%) dealt with new diseases, two (1%) with new side effects, three (2%) with new mechanisms and four (3%) were curiosities. A total of 59 (42%) reports were surgical, 64 (46%) non-surgical and 16 (12%) paraclinical. CONCLUSION: We found that most case reports published in Ugeskrift for Laeger were of speciality relevance and had an educational perspective. The journal may consider focusing on cases of more general educational relevance and should also consider whether the current form and language suit the aim and role of the various types of case reports.

Unbalanced reporting of benefits and harms in abstracts on rofecoxib.

PURPOSE: It was predicted from the mechanism of action that, compared to older non-steroidal anti-inflammatory drugs, rofecoxib (Vioxx) would reduce gastrointestinal bleeding, but also that it would increase the occurrence of cardiovascular thrombosis. From the patient's point of view, both effects are important and should be investigated and reported similarly. We studied how they have been reported over time. METHODS: We searched PubMed for abstracts on rofecoxib that commented on gastrointestinal bleeding or cardiovascular thrombosis or both. Two researchers, blinded to date of publication and authors, assessed the abstracts independently. We judged the authors' view on rofecoxib and comments on gastrointestinal bleeding and thrombosis as being favourable, neutral or unfavourable towards rofecoxib. RESULTS: We included 393 abstracts commenting on gastrointestinal bleeding (72%) and cardiovascular thrombosis (54%) or both. Before October 2000, all abstracts (n = 27) mentioned only gastrointestinal bleeding and 89% were positive towards rofecoxib. The year before the withdrawal of rofecoxib (October 2003 to September 2004) (n = 46), 59% of abstracts commented on gastrointestinal bleeding only, 17% on thrombosis only, 24% on both and 67% were still positive. From October 2006 to September 2007 (n = 54), 13% mentioned gastrointestinal bleeding, 54% thrombosis, 33% mentioned both and only 11% were positive. CONCLUSIONS: The reporting of benefits and harms was not balanced and changed markedly over time. Knowledge of increased risk of thrombosis existed early on, but the harms came into focus too late, when the drug was already withdrawn, and when tens of thousands of patients had been harmed unnecessarily.

Association between conflicts of interest and favourable recommendations in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews: systematic review.

OBJECTIVE: To investigate the association between conflicts of interest and favourable recommendations in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews. DESIGN: Systematic review. ELIGIBILITY CRITERIA: Studies that compared the association between conflicts of interest and favourable recommendations of drugs or devices (eg, recommending a drug) in clinical guidelines, advisory committee reports, opinion pieces (eg, editorials), or narrative reviews. DATA SOURCES: PubMed, Embase, Cochrane Methodology Register (from inception to February 2020), reference lists, Web of Science, and grey literature. DATA EXTRACTION AND ANALYSIS: Two authors independently extracted data and assessed the methodological quality of the studies. Pooled relative risks and 95% confidence intervals were estimated using random effects models (relative risk >1 indicates that documents with conflicts of interest more often had favourable recommendations than documents with no conflicts of interest). Financial and non-financial conflicts of interest were analysed separately, and the four types of documents were analysed separately (preplanned) and combined (post hoc). RESULTS: 21 studies that analysed 106 clinical guidelines, 1809 advisory committee reports, 340 opinion pieces, and 497 narrative reviews were included. Unpublished data were received for 11 studies (eight full datasets and three summary datasets). 15 studies showed risk of confounding because the compared documents could differ in factors other than conflicts of interest (eg, different drugs used for different populations). The relative risk for associations between financial conflicts of interest and favourable recommendations for clinical guidelines was 1.26 (95% confidence interval 0.93 to 1.69; four studies of 86 clinical guidelines), for advisory committee reports was 1.20 (0.99 to 1.45; four studies of 629 advisory committee reports), for opinion pieces was 2.62 (0.91 to 7.55; four studies of 284 opinion pieces), and for narrative reviews was 1.20 (0.97 to 1.49; four studies of 457 narrative reviews). An analysis of all four types of documents combined supported these findings (1.26, 1.09 to 1.44). In one study that investigated specialty interests, the association between including radiologists as authors of guidelines and recommending routine breast cancer was: relative risk 2.10, 95% confidence interval 0.92 to 4.77; 12 clinical guidelines). CONCLUSIONS: We interpret our findings to indicate that financial conflicts of interest are associated with favourable recommendations of drugs and devices in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews. Limitations of this review were risk of confounding in the included studies and the statistical imprecision of individual analyses of each document type. It is not certain whether non-financial conflicts of interest influence recommendations. SYSTEMATIC REVIEW REGISTRATION: Cochrane Methodology Review Protocol MR000040.

Industry-supported meta-analyses compared with meta-analyses with non-profit or no support: differences in methodological quality and conclusions.

BACKGROUND: Studies have shown that industry-sponsored meta-analyses of drugs lack scientific rigour and have biased conclusions. However, these studies have been restricted to certain medical specialities. We compared all industry-supported meta-analyses of drug-drug comparisons with those without industry support. METHODS: We searched PubMed for all meta-analyses that compared different drugs or classes of drugs published in 2004. Two authors assessed the meta-analyses and independently extracted data. We used a validated scale for judging the methodological quality and a binary scale for judging conclusions. We divided the meta-analyses according to the type of support in 3 categories: industry-supported, non-profit support or no support, and undeclared support. RESULTS: We included 39 meta-analyses. Ten had industry support, 18 non-profit or no support, and 11 undeclared support. On a 0-7 scale, the median quality score was 6 for meta-analyses with non-profit or no support and 2.5 for the industry-supported meta-analyses (P < 0.01). Compared with industry-supported meta-analyses, more meta-analyses with non-profit or no support avoided bias in the selection of studies (P = 0.01), more often stated the search methods used to find studies (P = 0.02), searched comprehensively (P < 0.01), reported criteria for assessing the validity of the studies (P = 0.02), used appropriate criteria (P = 0.04), described methods of allocation concealment (P = 0.05), described methods of blinding (P = 0.05), and described excluded patients (P = 0.08) and studies (P = 0.15). Forty percent of the industry-supported meta-analyses recommended the experimental drug without reservations, compared with 22% of the meta-analyses with non-profit or no support (P = 0.57).In a sensitivity analysis, we contacted the authors of the meta-analyses with undeclared support. Eight who replied that they had not received industry funding were added to those with non-profit or no support, and 3 who did not reply were added to those with industry support. This analysis did not change the results much. CONCLUSION: Transparency is essential for readers to make their own judgment about medical interventions guided by the results of meta-analyses. We found that industry-supported meta-analyses are less transparent than meta-analyses with non-profit support or no support.

Cognitive skills affect outcome of CI in children: A systematic review.

OBJECTIVE: To systematically review previous literature to determine to what extent hearing- impaired children with cognitive disabilities benefit from cochlear implantation (CI). Ultimately, to recommend guidelines for preoperative cognitive testing of hearing- impaired children and for the postoperative rehabilitation programs. METHODS: Pubmed, Cinahl, Embase, and The Cochrane Library was searched systematically for studies reporting cognitive disabilities in CI children. RESULTS: Seven hundred and sixty-three studies were discovered by the search of which 15 fulfilled the inclusion- and exclusion criteria. An overall correlation was evident regarding cognitive abilities and benefit of CI in hearing, speech and language development, and speech perception. DISCUSSION: Many of the eligible studies were case series with evidence level four. Furthermore, heterogeneity of studies impeded comparison between the preoperative cognitive tests and the postoperative outcome tests. However, studies agree that cognitive abilities in hearing- impaired children can predict outcome after CI. International guidelines for preoperative cognitive tests in different age groups, along with international guidelines for postoperative outcome tests are necessary for better inter-study comparison. CONCLUSION: The degree of preoperatively cognitive disabilities is associated with the outcome after CI, thereby emphasizing why accurate cognitive tests are an important part of the preoperative evaluation of CI and pre-requisite for shared decision making. Furthermore, individual postoperative rehabilitation programs must be created depending on the child's cognitive ability.

Comparison of results from different imputation techniques for missing data from an anti-obesity drug trial.

BACKGROUND: In randomised trials of medical interventions, the most reliable analysis follows the intention-to-treat (ITT) principle. However, the ITT analysis requires that missing outcome data have to be imputed. Different imputation techniques may give different results and some may lead to bias. In anti-obesity drug trials, many data are usually missing, and the most used imputation method is last observation carried forward (LOCF). LOCF is generally considered conservative, but there are more reliable methods such as multiple imputation (MI). OBJECTIVES: To compare four different methods of handling missing data in a 60-week placebo controlled anti-obesity drug trial on topiramate. METHODS: We compared an analysis of complete cases with datasets where missing body weight measurements had been replaced using three different imputation methods: LOCF, baseline carried forward (BOCF) and MI. RESULTS: 561 participants were randomised. Compared to placebo, there was a significantly greater weight loss with topiramate in all analyses: 9.5 kg (SE 1.17) in the complete case analysis (N = 86), 6.8 kg (SE 0.66) using LOCF (N = 561), 6.4 kg (SE 0.90) using MI (N = 561) and 1.5 kg (SE 0.28) using BOCF (N = 561). CONCLUSIONS: The different imputation methods gave very different results. Contrary to widely stated claims, LOCF did not produce a conservative (i.e., lower) efficacy estimate compared to MI. Also, LOCF had a lower SE than MI.

Quality of systematic reviews in pediatric oncology--a systematic review.

BACKGROUND: To ensure evidence-based decision making in pediatric oncology systematic reviews are necessary. The objective of our study was to evaluate the methodological quality of all currently existing systematic reviews in pediatric oncology. METHODS: We identified eligible systematic reviews through a systematic search of the literature. Data on clinical and methodological characteristics of the included systematic reviews were extracted. The methodological quality of the included systematic reviews was assessed using the overview quality assessment questionnaire, a validated 10-item quality assessment tool. We compared the methodological quality of systematic reviews published in regular journals with that of Cochrane systematic reviews. RESULTS: We included 117 systematic reviews, 99 systematic reviews published in regular journals and 18 Cochrane systematic reviews. The average methodological quality of systematic reviews was low for all ten items, but the quality of Cochrane systematic reviews was significantly higher than systematic reviews published in regular journals. On a 1-7 scale, the median overall quality score for all systematic reviews was 2 (range 1-7), with a score of 1 (range 1-7) for systematic reviews in regular journals compared to 6 (range 3-7) in Cochrane systematic reviews (p<0.001). CONCLUSION: Most systematic reviews in the field of pediatric oncology seem to have serious methodological flaws leading to a high risk of bias. While Cochrane systematic reviews were of higher methodological quality than systematic reviews in regular journals, some of them also had methodological problems. Therefore, the methodology of each individual systematic review should be scrutinized before accepting its results.

Disagreements in meta-analyses using outcomes measured on continuous or rating scales: observer agreement study.

OBJECTIVE: To study the inter-observer variation related to extraction of continuous and numerical rating scale data from trial reports for use in meta-analyses. DESIGN: Observer agreement study. DATA SOURCES: A random sample of 10 Cochrane reviews that presented a result as a standardised mean difference (SMD), the protocols for the reviews and the trial reports (n=45) were retrieved. DATA EXTRACTION: Five experienced methodologists and five PhD students independently extracted data from the trial reports for calculation of the first SMD result in each review. The observers did not have access to the reviews but to the protocols, where the relevant outcome was highlighted. The agreement was analysed at both trial and meta-analysis level, pairing the observers in all possible ways (45 pairs, yielding 2025 pairs of trials and 450 pairs of meta-analyses). Agreement was defined as SMDs that differed less than 0.1 in their point estimates or confidence intervals. RESULTS: The agreement was 53% at trial level and 31% at meta-analysis level. Including all pairs, the median disagreement was SMD=0.22 (interquartile range 0.07-0.61). The experts agreed somewhat more than the PhD students at trial level (61% v 46%), but not at meta-analysis level. Important reasons for disagreement were differences in selection of time points, scales, control groups, and type of calculations; whether to include a trial in the meta-analysis; and data extraction errors made by the observers. In 14 out of the 100 SMDs calculated at the meta-analysis level, individual observers reached different conclusions than the originally published review. CONCLUSIONS: Disagreements were common and often larger than the effect of commonly used treatments. Meta-analyses using SMDs are prone to observer variation and should be interpreted with caution. The reliability of meta-analyses might be improved by having more detailed review protocols, more than one observer, and statistical expertise.

[Cochrane reviews compared with industry-supported and other meta-analyses of the same drugs--secondary publication]. / Cochraneoversigter sammenlignet med firmastøttede og andre metaanalyser af de samme laegemidler.

24 Cochrane reviews were compared with other, closely matched, meta-analyses of the same drugs. The quality score was highest for Cochrane reviews (7 vs. 2, p < 0.01). Of 8 industry-supported reviews, 7 with conclusions all recommended the experimental drug without reservations, compared with none of the Cochrane reviews (p = 0.02) although the estimated treatment effect was similar on average (p = 0.64). Industry-supported reviews were less transparent, had few reservations about methodological limitations of the included trials, and should be read with caution.

Cochrane reviews compared with industry supported meta-analyses and other meta-analyses of the same drugs: systematic review.

OBJECTIVE: To compare the methodological quality and conclusions in Cochrane reviews with those in industry supported meta-analyses and other meta-analyses of the same drugs. DESIGN: Systematic review comparing pairs of meta-analyses that studied the same two drugs in the same disease and were published within two years of each other. DATA SOURCES: Cochrane Database of Systematic Reviews (2003, issue 1), PubMed, and Embase. DATA EXTRACTION: Two observers independently extracted data and used a validated scale to judge the methodological quality of the reviews. RESULTS: 175 of 1596 Cochrane reviews had a meta-analysis that compared two drugs. Twenty four meta-analyses that matched the Cochrane reviews were found: eight were industry supported, nine had undeclared support, and seven had no support or were supported by non-industry sources. On a 0-7 scale, the median quality score was 7 for Cochrane reviews and 3 for other reviews (P < 0.01). Compared with industry supported reviews and reviews with undeclared support, Cochrane reviews had more often considered the potential for bias in the review--for example, by describing the method of concealment of allocation and describing excluded patients or studies. The seven industry supported reviews that had conclusions recommended the experimental drug without reservations, compared with none of the Cochrane reviews (P = 0.02), although the estimated treatment effect was similar on average (z = 0.46, P = 0.64). Reviews with undeclared support and reviews with not for profit support or no support had conclusions that were similar in cautiousness to the Cochrane reviews. CONCLUSIONS: Industry supported reviews of drugs should be read with caution as they were less transparent, had few reservations about methodological limitations of the included trials, and had more favourable conclusions than the corresponding Cochrane reviews.