Barbara Mintzes

BACKGROUND: Clinical research affecting how doctors practice medicine is increasingly sponsored by companies that make drugs and medical devices. Previous systematic reviews have found that pharmaceutical-industry sponsored studies are more often favorable to the sponsor's product compared with studies with other sources of sponsorship. A similar association between sponsorship and outcomes have been found for device studies, but the body of evidence is not as strong as for sponsorship of drug studies. This review is an update of a previous Cochrane review and includes empirical studies on the association between sponsorship and research outcome. OBJECTIVES: To investigate whether industry sponsored drug and device studies have more favorable outcomes and differ in risk of bias, compared with studies having other sources of sponsorship. SEARCH METHODS: In this update we searched MEDLINE (2010 to February 2015), Embase (2010 to February 2015), the Cochrane Methodology Register (2015, Issue 2) and Web of Science (June 2015). In addition, we searched reference lists of included papers, previous systematic reviews and author files. SELECTION CRITERIA: Cross-sectional studies, cohort studies, systematic reviews and meta-analyses that quantitatively compared primary research studies of drugs or medical devices sponsored by industry with studies with other sources of sponsorship. We had no language restrictions. DATA COLLECTION AND ANALYSIS: Two assessors screened abstracts and identified and included relevant papers. Two assessors extracted data, and we contacted authors of included papers for additional unpublished data. Outcomes included favorable results, favorable conclusions, effect size, risk of bias and whether the conclusions agreed with the study results. Two assessors assessed risk of bias of included papers. We calculated pooled risk ratios (RR) for dichotomous data (with 95% confidence intervals (CIs)). MAIN RESULTS: Twenty-seven new papers were included in this update and in total the review contains 75 included papers. Industry sponsored studies more often had favorable efficacy results, RR: 1.27 (95% CI: 1.17 to 1.37) (25 papers) (moderate quality evidence), similar harms results RR: 1.37 (95% CI: 0.64 to 2.93) (four papers) (very low quality evidence) and more often favorable conclusions RR: 1.34 (95% CI: 1.19 to 1.51) (29 papers) (low quality evidence) compared with non-industry sponsored studies. Nineteen papers reported on sponsorship and efficacy effect size, but could not be pooled due to differences in their reporting of data and the results were heterogeneous. We did not find a difference between drug and device studies in the association between sponsorship and conclusions (test for interaction, P = 0.98) (four papers). Comparing industry and non-industry sponsored studies, we did not find a difference in risk of bias from sequence generation, allocation concealment, follow-up and selective outcome reporting. However, industry sponsored studies more often had low risk of bias from blinding, RR: 1.25 (95% CI: 1.05 to 1.50) (13 papers), compared with non-industry sponsored studies. In industry sponsored studies, there was less agreement between the results and the conclusions than in non-industry sponsored studies, RR: 0.83 (95% CI: 0.70 to 0.98) (six papers). AUTHORS' CONCLUSIONS: Sponsorship of drug and device studies by the manufacturing company leads to more favorable efficacy results and conclusions than sponsorship by other sources. Our analyses suggest the existence of an industry bias that cannot be explained by standard 'Risk of bias' assessments.

BACKGROUND: Systematic reviews, which assess the risk of bias in included studies, are increasingly used to develop environmental hazard assessments and public health guidelines. These research areas typically rely on evidence from human observational studies of exposures, yet there are currently no universally accepted standards for assessing risk of bias in such studies. The risk of bias in non-randomised studies of exposures (ROBINS-E) tool has been developed by building upon tools for risk of bias assessment of randomised trials, diagnostic test accuracy studies and observational studies of interventions. This paper reports our experience with the application of the ROBINS-E tool. METHODS: We applied ROBINS-E to 74 exposure studies (60 cohort studies, 14 case-control studies) in 3 areas: environmental risk, dietary exposure and drug harm. All investigators provided written feedback, and we documented verbal discussion of the tool. We inductively and iteratively classified the feedback into 7 themes based on commonalities and differences until all the feedback was accounted for in the themes. We present a description of each theme. RESULTS: We identified practical concerns with the premise that ROBINS-E is a structured comparison of the observational study being rated to the 'ideal' randomised controlled trial. ROBINS-E assesses 7 domains of bias, but relevant questions related to some critical sources of bias, such as exposure and funding source, are not assessed. ROBINS-E fails to discriminate between studies with a single risk of bias or multiple risks of bias. ROBINS-E is severely limited at determining whether confounders will bias study outcomes. The construct of co-exposures was difficult to distinguish from confounders. Applying ROBINS-E was time-consuming and confusing. CONCLUSIONS: Our experience suggests that the ROBINS-E tool does not meet the need for an international standard for evaluating human observational studies for questions of harm relevant to public and environmental health. We propose that a simpler tool, based on empirical evidence of bias, would provide accurate measures of risk of bias and is more likely to meet the needs of the environmental and public health community.

BACKGROUND: Direct-to-consumer advertising (DTCA) of prescription drugs has increased rapidly in the United States during the last decade, yet little is known about its effects on prescribing decisions in primary care. We compared prescribing decisions in a US setting with legal DTCA and a Canadian setting where DTCA of prescription drugs is illegal, but some cross-border exposure occurs. METHODS: We recruited primary care physicians working in Sacramento, California, and Vancouver, British Columbia, and their group practice partners to participate in the study. On pre- selected days, patients aged 18 years or more completed a questionnaire before seeing their physician. We asked these patients' physicians to complete a brief questionnaire immediately following the selected patient visit. By pairing individual patient and physician responses, we determined how many patients had been exposed to some form of DTCA, the frequency of patients' requests for prescriptions for advertised medicines and the frequency of prescriptions that were stimulated by the patients' requests. We measured physicians' confidence in treatment choice for each new prescription by asking them whether they would prescribe this drug to a patient with the same condition. RESULTS: Seventy-eight physicians (Sacramento n = 38, Vancouver n = 40) and 1431 adult patients (Sacramento n = 683, Vancouver n = 748), or 61% of patients who consulted participating physicians on pre-set days, participated in the survey. Exposure to DTCA was higher in Sacramento, although 87.4% of Vancouver patients had seen prescription drug advertisements. Of the Sacramento patients, 7.2% requested advertised drugs as opposed to 3.3% in Vancouver (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.2-4.1). Patients with higher self- reported exposure to advertising, conditions that were potentially treatable by advertised drugs, and/or greater reliance on advertising requested more advertised medicines. Physicians fulfilled most requests for DTCA drugs (for 72% of patients in Vancouver and 78% in Sacramento); this difference was not statistically significant. Patients who requested DTCA drugs were much more likely to receive 1 or more new prescriptions (for requested drugs or alternatives) than those who did not request DTCA drugs (OR 16.9, 95% CI 7.5-38.2). Physicians judged 50.0% of new prescriptions for requested DTCA drugs to be only "possible" or "unlikely" choices for other similar patients, as compared with 12.4% of new prescriptions not requested by patients (p < 0.001). INTERPRETATION: Our results suggest that more advertising leads to more requests for advertised medicines, and more prescriptions. If DTCA opens a conversation between patients and physicians, that conversation is highly likely to end with a prescription, often despite physician ambivalence about treatment choice.

Only the United States and New Zealand allow advertising of prescription drugs directed at patients. US spending on such advertising grew rapidly during the 1990s, reaching $2.47bn (1650m) in 2000. 1 The dramatic increase in investment by the US pharmaceutical industry is evidence of an expected effect on sales. On the rationale that such advertising provides important information to consumers and patients who may benefit from advertised products, pharmaceutical manufacturers have campaigned in the European Union 2 and Canada 3 for the relaxing of current regulatory restrictions. We examined the relation between direct to consumer advertising and patients' requests for prescriptions and the relation between patients' requests and prescribing decisions.