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Background: Little is known about publication agreements between industry and academic investigators in trial protocols and the consistency of these agreements with corresponding statements in publications. We aimed to investigate (i) the existence and types of publication agreements in trial protocols, (ii) the completeness and consistency of the reporting of these agreements in subsequent publications, and (iii) the frequency of co-authorship by industry employees.Methods and Findings: We used a retrospective cohort of randomized clinical trials (RCTs) based on archived protocols approved by six research ethics committees between 13 January 2000 and 25 November 2003. Only RCTs with industry involvement were eligible. We investigated the documentation of publication agreements in RCT protocols and statements in corresponding journal publications. Of 647 eligible RCT protocols, 456 (70.5%) mentioned an agreement regarding publication of results. Of these 456, 393 (86.2%) documented an industry partner's right to disapprove or at least review proposed manuscripts; 39 (8.6%) agreements were without constraints of publication. The remaining 24 (5.3%) protocols referred to separate agreement documents not accessible to us. Of those 432 protocols with an accessible publication agreement, 268 (62.0%) trials were published. Most agreements documented in the protocol were not reported in the subsequent publication (197/268 [73.5%]). Of 71 agreements reported in publications, 52 (73.2%) were concordant with those documented in the protocol. In 14 of 37 (37.8%) publications in which statements suggested unrestricted publication rights, at least one co-author was an industry employee. In 25 protocol-publication pairs, author statements in publications suggested no constraints, but 18 corresponding protocols documented restricting agreements.Conclusions: Publication agreements constraining academic authors' independence are common. Journal articles seldom report on publication agreements, and, if they do, statements can be discrepant with the trial protocol. [ABSTRACT FROM AUTHOR]

Background: Patients with serious illness, and their families, state that better communication and decision-making with healthcare providers is a high priority to improve the quality of end-of-life care. Numerous communication tools to assist patients, family members, and clinicians in end-of-life decision-making have been published, but their effectiveness remains unclear. Objectives: To determine, amongst adults in ambulatory care settings, the effect of structured communication tools for end-of-life decision-making on completion of advance care planning. Methods: We searched for relevant randomized controlled trials (RCTs) or non-randomized intervention studies in MEDLINE, EMBASE, CINAHL, ERIC, and the Cochrane Database of Randomized Controlled Trials from database inception until July 2014. Two reviewers independently screened articles for eligibility, extracted data, and assessed risk of bias. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to evaluate the quality of evidence for each of the primary and secondary outcomes. Results: Sixty-seven studies, including 46 RCTs, were found. The majority evaluated communication tools in older patients (age >50) with no specific medical condition, but many specifically evaluated populations with cancer, lung, heart, neurologic, or renal disease. Most studies compared the use of communication tools against usual care, but several compared the tools to less-intensive advance care planning tools. The use of structured communication tools increased: the frequency of advance care planning discussions/discussions about advance directives (RR 2.31, 95% CI 1.25–4.26, p = 0.007, low quality evidence) and the completion of advance directives (ADs) (RR 1.92, 95% CI 1.43–2.59, p<0.001, low quality evidence); concordance between AD preferences and subsequent medical orders for use or non-use of life supporting treatment (RR 1.19, 95% CI 1.01–1.39, p = 0.028, very low quality evidence, 1 observational study); and concordance between the care desired and care received by patients (RR 1.17, 95% CI 1.05–1.30, p = 0.004, low quality evidence, 2 RCTs). Conclusions: The use of structured communication tools may increase the frequency of discussions about and completion of advance directives, and concordance between the care desired and the care received by patients. The use of structured communication tools rather than an ad-hoc approach to end-of-life decision-making should be considered, and the selection and implementation of such tools should be tailored to address local needs and context. Registration: PROSPERO [ABSTRACT FROM AUTHOR]

Background: Investigators often face challenges when recruiting participants into randomized controlled trials (RCTs). Some data suggest that telephone reminders may lead to greater participant enrollment. Methods: Patients aged 50 to 70 years from family practice rosters were initially mailed invitations to participate in an RCT of colorectal cancer screening. Patients who did not respond were randomly allocated to follow-up invitations by either telephone or mail four weeks after the initial invitation. The primary outcome was attendance for eligibility screening with the study nurse. Results: After mailing invitations to 1,348 patients, 104 patients were initially enrolled in the RCT of colon cancer screening. Of 952 patients who did not respond to the initial mailed invitation, we randomly allocated 480 to follow-up invitation by telephone and 472 to follow-up invitation by mail. Attendance for eligibility screening with the study nurse was more frequent when non-responders were followed-up by telephone (84/480, 17.5%) than by mail (43/472, 9.1%) (relative risk (RR) 1.92, 95% confidence interval (CI) 1.36 to 2.71, P < 0.001). Enrollment into the RCT was also greater among patients followed-up by telephone (59/480, 12.3%) compared to those followed-up by mail (35/472, 7.4%) (RR 1.66, 95% CI 1.11 to 2.47, P=0.01). Conclusions: Telephone-based follow-up results in greater enrollment compared to a mail-based method. Our findings should be of interest to investigators conducting RCTs, particularly trials of screening interventions involving asymptomatic participants for which volunteer participation may be challenging. [ABSTRACT FROM AUTHOR]

The article offers information on the method to use noninferiority clinical trials. It states that clinical investigators are more concern for testing treatments that have primary benefit of less burden or harms to an existing trial standard. It highlights several issue related to validity, interpretation, and applicability of results which are specific for non-inferiority trials. It further mentions that wrong results in non-inferiority trials is often aquired by suboptimal administration of standard treatment. Photograph depicting possible outcomes of result in non-inferiority trials is also presented.

Background: Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs. Methods/Design: Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs. We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment. Discussion: Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements. [ABSTRACT FROM AUTHOR]

Objective To investigate the association between treatment induced change in high density lipoprotein cholesterol and total death, coronary heart disease death, and coronary heart disease events (coronary heart disease death and non-fatal myocardial infarction) adjusted for changes in low density lipoprotein cholesterol and drug class in randomised trials of lipid modifying interventions. Design Systematic review and meta-regression analysis of randomised controlled trials. Data sources Medline, Embase, Central, CINAHL, and AMED to October 2006 supplemented by contact with experts in the field. Study selection In teams of two, reviewers independently determined eligibility of randomised trialsthattested lipid modifying interventions to reduce cardiovascular risk, reported high density lipoprotein cholesterol and mortality or myocardial infarctions separately for treatment groups, and treated and followed participants for at least six months. Data extraction and synthesis Using standardised, pre- piloted forms, reviewers independently extracted relevant information from each article. The change in lipid concentrations for each trial and the weighted risk ratios for clinical outcomes were calculated. Results The meta-regression analysis included 108 randomised trials involving 299 310 participants at risk ol cardiovascular events. All analyses that adjusted for changes in low density lipoprotein cholesterol showed no association between treatment induced change in high density lipoprotein cholesterol and risk ratios for coronary heart disease deaths, coronary heart disease events, or total deaths. With all trials included, change in high . density lipoprotein cholesterol explained almost no variability (<1%) in any of the outcomes. The change in the quotient of low density lipoprotein cholesterol and high ' density lipoprotein cholesterol did not explain more of the variability in any of the outcomes than did the change in low density lipoprotein cholesterqlalone. For a 10 mg/dl (0.26 mmol/l) reduction in low density lipoprotein cholesterol, the relative risk reduction was 7.2%(95% confidence interval 3.1% to 11%; P=0.001) for coronary heart disease deaths, 7.1% (4.5% to 9.8%; P<0.001) for coronary heart disease events, and 4.4% (1.6% to 7.2%; P=0.002) for total deaths, when adjusted for change in high density lipoprotein cholesterol and drug class. Conclusions Available data suggest that simply increasing the amount of circulating high density lipoprotein cholesterol does not reduce the risk of coronary heart disease events, coronary heart disease deaths, or total deaths. The results support reduction in low density lipoprotein cholesterol as the primary goal for lipid modifying interventions. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To determine the effects of formatting alternatives in Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence profiles on guideline panelists’ preferences, comprehension, and accessibility. Study Design and Setting: We randomized 116 antithrombotic therapy guideline panelists to review one of two table formats with four formatting alternatives. After answering relevant questions, panelists reviewed the other format and reported their preferences for specific formatting alternatives. Results: Panelists (88 of 116 invited [76%]) preferred presentation of study event rates over no study event rates (median 1 [interquartile range (IQR) 1] on 1–7 scale), absolute risk differences over absolute risks (median 2 [IQR 3]), and additional information in table cells over footnotes (median 1 [IQR 2]). Panelists presented with time frame information in the tables, and not only in footnotes, were more likely to correctly answer questions regarding time frame (58% vs. 11%, P <0.0001), and those presented with risk differences and not absolute risks were more likely to correctly interpret confidence intervals for absolute effects (95% vs. 54%, P <0.0001). Information was considered easy to find, easy to comprehend, and helpful in making recommendations regardless of table format (median 6, IQR 0–1). Conclusion: Panelists found information in GRADE evidence profiles accessible. Correct comprehension of some key information was improved by providing additional information in table and presenting risk differences. [Copyright &y& Elsevier]

Abstract: Objective: To test the reliability and validity of specific instructions to classify blinding, when unclearly reported in randomized trials, as “probably done” or “probably not done.” Study Design and Setting: We assessed blinding of patients, health care providers, data collectors, outcome adjudicators, and data analysts in 233 randomized trials in duplicate and independently using detailed instructions. The response options were “definitely yes,” “probably yes,” “probably no,” and “definitely no.” We contacted authors for data verification (46% response). For each of the five questions, we assessed reliability by calculating the agreement between the two reviewers and validity by calculating the agreement between reviewers’ consensus and verified data. Results: The percentage with unclear blinding status varied between 48.5% (patients) and 84.1% (data analysts). Reliability was moderate for blinding of outcome adjudicators (κ =0.52) and data analysts (κ =0.42) and substantial for blinding of patients (κ =0.71), providers (κ =0.68), and data collectors (κ =0.65). The raw agreement between the consensus record and the author-verified record varied from 84.1% (blinding of data analysts) to 100% (blinding of health care providers). Conclusion: With the possible exception of blinding of data analysts, use of “probably yes” and “probably no” instead of “unclear” may enhance the assessment of blinding in trials. [Copyright &y& Elsevier]