Roberta W. Scherer

Outcome Reporting in Industry-Sponsored Trials of Gabapentin for Off-Label Use

BACKGROUND There is good evidence of selective outcome reporting in published reports of randomized trials. METHODS We examined reporting practices for trials of gabapentin funded by Pfizer and Warner-Lamberts subsidiary, Parke-Davis (hereafter referred to as Pfizer and Parke-Davis) for off-label indications (prophylaxis against migraine and treatment of bipolar disorders, neuropathic pain, and nociceptive pain), comparing internal company documents with published reports. RESULTS We identified 20 clinical trials for which internal documents were available from Pfizer and Parke-Davis; of these trials, 12 were reported in publications. For 8 of the 12 reported trials, the primary outcome defined in the published report differed from that described in the protocol. Sources of disagreement included the introduction of a new primary outcome (in the case of 6 trials), failure to distinguish between primary and secondary outcomes (2 trials), relegation of primary outcomes to secondary outcomes (2 trials), and failure to report one or more protocol-defined primary outcomes (5 trials). Trials that presented findings that were not significant (P > or = 0.05) for the protocol-defined primary outcome in the internal documents either were not reported in full or were reported with a changed primary outcome. The primary outcome was changed in the case of 5 of 8 published trials for which statistically significant differences favoring gabapentin were reported. Of the 21 primary outcomes described in the protocols of the published trials, 6 were not reported at all and 4 were reported as secondary outcomes. Of 28 primary outcomes described in the published reports, 12 were newly introduced. CONCLUSIONS We identified selective outcome reporting for trials of off-label use of gabapentin. This practice threatens the validity of evidence for the effectiveness of off-label interventions.

Hysterectomy Compared With Endometrial Ablation for Dysfunctional Uterine Bleeding : A Randomized Controlled Trial

OBJECTIVE: To compare the effectiveness of hysterectomy and endometrial ablation in women with dysfunctional uterine bleeding. METHODS: The Surgical Treatments Outcomes Project for Dysfunctional Uterine Bleeding was a multicenter, randomized controlled trial. Eligible women were premenopausal with dysfunctional uterine bleeding and aged 18 years or older. Primary outcomes were problems that led the woman to seek care solved, bleeding, pain, and fatigue at 12 months. Additional outcomes included quality of life, adverse events, reoperation, and others at 24 months and up to 5 years. RESULTS: We randomly assigned 237 women between January 1998 and June 2001. Follow-up ended in June 2003. We completed 24 months of follow-up on 114 of 123 women assigned to endometrial ablation and 111 of 114 assigned to hysterectomy. Approximately 85% of women were aged younger than 45 years; 76.4% classified themselves as white, 18.6% as African American, less than 1% as Asian, 4.6% as American Indian, and 8.4% as Hispanic (classification within more than one category possible). Both endometrial ablation and hysterectomy were effective at 24 months in solving the problem that led women to seek care (84.9% compared with 94.4%), and in relieving bleeding, pain, fatigue, and other symptoms, although hysterectomy was more effective for bleeding. By 48 months, 32 of the 110 women initially receiving endometrial ablation required reoperation. Adverse events were more frequent with hysterectomy. CONCLUSION: Both endometrial ablation and hysterectomy are effective treatments in women with dysfunctional uterine bleeding. Hysterectomy (as the index surgery) was associated with more adverse events and a substantial number of patients receiving endometrial ablation had reoperation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00114088 LEVEL OF EVIDENCE: I

Extent of Non-Publication in Cohorts of Studies Approved by Research Ethics Committees or Included in Trial Registries

Background The synthesis of published research in systematic reviews is essential when providing evidence to inform clinical and health policy decision-making. However, the validity of systematic reviews is threatened if journal publications represent a biased selection of all studies that have been conducted (dissemination bias). To investigate the extent of dissemination bias we conducted a systematic review that determined the proportion of studies published as peer-reviewed journal articles and investigated factors associated with full publication in cohorts of studies (i) approved by research ethics committees (RECs) or (ii) included in trial registries. Methods and Findings Four bibliographic databases were searched for methodological research projects (MRPs) without limitations for publication year, language or study location. The searches were supplemented by handsearching the references of included MRPs. We estimated the proportion of studies published using prediction intervals (PI) and a random effects meta-analysis. Pooled odds ratios (OR) were used to express associations between study characteristics and journal publication. Seventeen MRPs (23 publications) evaluated cohorts of studies approved by RECs; the proportion of published studies had a PI between 22% and 72% and the weighted pooled proportion when combining estimates would be 46.2% (95% CI 40.2%–52.4%, I2 = 94.4%). Twenty-two MRPs (22 publications) evaluated cohorts of studies included in trial registries; the PI of the proportion published ranged from 13% to 90% and the weighted pooled proportion would be 54.2% (95% CI 42.0%–65.9%, I2 = 98.9%). REC-approved studies with statistically significant results (compared with those without statistically significant results) were more likely to be published (pooled OR 2.8; 95% CI 2.2–3.5). Phase-III trials were also more likely to be published than phase II trials (pooled OR 2.0; 95% CI 1.6–2.5). The probability of publication within two years after study completion ranged from 7% to 30%. Conclusions A substantial part of the studies approved by RECs or included in trial registries remains unpublished. Due to the large heterogeneity a prediction of the publication probability for a future study is very uncertain. Non-publication of research is not a random process, e.g., it is associated with the direction of study findings. Our findings suggest that the dissemination of research findings is biased.

Are Exercise Programs Effective for Improving Health-Related Quality of Life Among Cancer Survivors? A Systematic Review and Meta-Analysis

PURPOSE/OBJECTIVES To evaluate the effectiveness of exercise interventions on overall health-related quality of life (HRQOL) and its domains among cancer survivors who have completed primary treatment. DATA SOURCES 11 electronic databases were searched from inception (dates varied) to October 2011. The authors also identified eligible trials through a search of additional sources. DATA SYNTHESIS 40 trials with 3,694 participants met the inclusion criteria. At 12 weeks, cancer survivors exposed to exercise interventions had greater positive improvement in overall HRQOL (standardized mean difference [SMD] 0.48; 95% confidence interval [CI] [0.16, 0.81]), emotional well-being (SMD 0.33; 95% CI [0.05, 0.61]), and social functioning (SMD 0.45; 95% CI [0.02, 0.87]); and had a significant reduction in anxiety (SMD -0.26; 95% CI [-0.44, -0.07]) and fatigue (SMD -0.82; 95% CI [-1.5, -0.14]). CONCLUSIONS Exercise programs have a beneficial effect on HRQOL and most of its domains and can be integrated into the management plans for cancer survivors who have completed treatment. Future research is needed to help understand specific attributes of exercise programs that are beneficial for improving HRQOL within and across cancer types. IMPLICATIONS FOR NURSING Evidence presented in this review supports the inclusion of exercise programs in clinical guidelines for the management of cancer survivors who have completed treatment, such as the Oncology Nursing Societys Putting Evidence Into Practice resource.

A survey of frameworks for best practices in weight-of-evidence analyses

Abstract The National Academy of Sciences (NAS) Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde proposed a “roadmap” for reform and improvement of the Agency’s risk assessment process. Specifically, it called for development of a transparent and defensible methodology for weight-of-evidence (WoE) assessments. To facilitate development of an improved process, we developed a white paper that reviewed approximately 50 existing WoE frameworks, seeking insights from their variations and nominating best practices for WoE analyses of causation of chemical risks. Four phases of WoE analysis were identified and evaluated in each framework: (1) defining the causal question and developing criteria for study selection, (2) developing and applying criteria for review of individual studies, (3) evaluating and integrating evidence and (4) drawing conclusions based on inferences. We circulated the draft white paper to stakeholders and then held a facilitated, multi-disciplinary invited stakeholder workshop to broaden and deepen the discussion on methods, rationales, utility and limitations among the surveyed WoE frameworks. The workshop developed recommendations for improving the conduct of WoE evaluations. Based on the analysis of the 50 frameworks and discussions at the workshop, best practices in conducting WoE analyses were identified for each of the four phases. Many of these best practices noted from the analysis and workshop could be implemented immediately, while others may require additional refinement as part of the ongoing discussions for improving the scientific basis of chemical risk assessments.

Assessment of Risk of Bias Among Pediatric Randomized Controlled Trials

OBJECTIVE: The goal was to assess the risk of bias among pediatric, randomized, controlled trials (RCTs) reported in 8 high-impact journals. METHODS: We searched PubMed for all pediatric RCTs reported between July 1, 2007, and June 30, 2008, in 8 journals with high impact factors. Using Cochrane Collaboration methods for risk assessment, we evaluated all reports for risk of bias according to domain (ie, randomized sequence generation, allocation concealment, masking, incomplete outcome data, selective outcome reporting, and other). We used multiple logistic regression to test for associations between the presence of a high risk of bias according to domain and funding source, intervention type, trial registration, and multicenter status. RESULTS: Industry-funded RCTs were more likely to show a high risk of bias for sequence generation, compared with government-funded RCTs (adjusted odds ratio [aOR]: 6.1 [95% confidence interval [CI]: 1.70– 21.89]), and behavioral/educational trials were more likely to show a high risk of bias for sequence generation (aOR: 2.8 [95% CI: 1.06–7.36]) and allocation concealment (aOR: 4.09 [95% CI: 1.69–9.90]), compared with drug trials. Registered trials were less likely to have a high risk of bias for sequence generation, compared with nonregistered trials (aOR: 0.33 [95% CI: 0.15–0.71]). CONCLUSIONS: Overall, we found a large proportion of pediatric RCT reports with a high risk of bias for sequence generation and allocation concealment. Factors associated with a high risk of bias included industry funding and assessment of behavioral/educational interventions, whereas trial registration was associated with a lower risk of bias.

Cigarette Smoking and Incident Chronic Kidney Disease: A Systematic Review

Background: Several studies have examined the role of cigarette smoking in the development of renal disease in human populations. However, there have been no systematic reviews on the evidence linking smoking with incident renal disease. Methods: We performed an evidence-based evaluation of peer-reviewed research published during 1966–2005, from a search of five databases, including Ovid MEDLINE and EMBASE. Results: Of the 28 studies that were reviewed, 11 were excluded from the final analysis due to poor methodological quality (n = 6), no reported risk estimate for the association between smoking and kidney disease (n = 3), inability to find a Japanese translator (n = 1), and duplicate cohort (n = 1). Seventeen studies were included in the final analysis; seven studies found an overall significant association between smoking and incident chronic kidney disease, and three studies found a significantly increased risk of chronic kidney disease in current smokers that was gender and/or dose related. An increased risk of developing chronic kidney disease among smokers was significantly associated with male gender (relative risk 2.4, 95% confidence interval 1.2–4.5), >20 cigarettes smoked/day (odds ratio 1.51, 95% confidence interval 1.06–2.15, and relative risk 2.3, 95% confidence interval 1.2–4.3), and smoking >40 years (odds ratio 1.45, 95% confidence interval 1.00–2.09). A pooled estimate of the relative risk (meta-analysis) was deemed inappropriate due to the heterogeneity in methodologies utilized by the different studies. Conclusions: This comprehensive review reveals overall evidence for current cigarette smoking as a risk factor for incident chronic kidney disease. Further investigation is needed to more carefully examine the strength of the association between cigarette smoking and incident kidney disease.

The effectiveness of exercise interventions for improving health-related quality of life from diagnosis through active cancer treatment.

PURPOSE/OBJECTIVES To evaluate the effectiveness of exercise interventions on overall health-related quality of life (HRQOL) and its domains among adults scheduled to, or actively undergoing, cancer treatment. DATA SOURCES 11 electronic databases were searched through November 2011. In addition, the authors searched PubMeds related article feature, trial registries, and reference lists of included trials and related reviews. DATA SYNTHESIS 56 trials with 4,826 participants met the inclusion criteria. At 12 weeks, people exposed to exercise interventions had greater improvement in overall HRQOL, physical functioning, role functioning, social functioning, and fatigue. Improvement in HRQOL was associated with moderate-to-vigorous intensity exercise interventions. CONCLUSIONS Exercise can be a useful tool for managing HRQOL and HRQOL domains for people scheduled to, or actively undergoing, cancer treatment. More methodologically rigorous trials are needed to examine the attributes of exercise programs most effective for improving HRQOL. IMPLICATIONS FOR NURSING Evidence from this review supports the incorporation of exercise programs of moderate-to-vigorous intensity for the management of HRQOL among people scheduled to, or actively undergoing, cancer treatment into clinical guidelines through the Oncology Nursing Societys Putting Evidence Into Practice resources.

Assessing The Comparative Effectiveness Of A Diagnostic Technology: CT Colonography

Medical imaging is a prime example of an innovation that has brought important advances to medical care while triggering concerns about potential overuse and excessive costs. Many hopes are riding on comparative effectiveness research to help guide better decision making to improve quality and value. But the dynamic nature of medical imaging poses challenges for the traditional paradigms of evidentiary review and analysis at the heart of comparative effectiveness. This paper discusses these challenges and presents policy lessons for manufacturers, evidence reviewers, and decisionmakers, illustrated by an assessment of a prominent emerging imaging technique: computed tomography (CT) colonography.

Effect of methylphenidate on attention in apathetic AD patients in a randomized, placebo-controlled trial.

BACKGROUND Little is known about the effect of methylphenidate (MPH) on attention in Alzheimers disease (AD). MPH has shown to improve apathy in AD, and both apathy and attention have been related to dopaminergic function. The goal was to investigate MPH effects on attention in AD and assess the relationship between attention and apathy responses. METHODS MPH (10 mg PO twice daily) or placebo was administered for six weeks in a randomized, double-blind trial in mild-to-moderate AD outpatients with apathy (Neuropsychiatric Inventory (NPI) Apathy ≥ 4). Attention was measured with the Wechsler Adult Intelligence Scale--Digit Span (DS) subtest (DS forward, selective attention) and apathy with the Apathy Evaluation Scale (AES). A mixed effects linear regression estimated the difference in change from baseline between treatment groups, defined as δ (MPH (DS week 6-DS baseline)) - (placebo (DS week 6-DS baseline)). RESULTS In 60 patients (37 females, age = 76 ± 8, Mini-Mental State Examination (MMSE) = 20 ± 5, NPI Apathy = 7 ± 2), the change in DS forward (δ = 0.87 (95% CI: 0.06-1.68), p = 0.03) and DS total (δ = 1.01 (95% CI: 0.09-1.93), p = 0.03) favored MPH over placebo. Of 57 completers, 17 patients had improved apathy (≥3.3 points on the AES from baseline to end point) and 40 did not. There were no significant associations between AES and NPI Apathy with DS change scores in the MPH, placebo, AES responder, or non-responder groups. DS scores did not predict apathy response to MPH treatment. CONCLUSION These results suggest MPH can improve attention and apathy in AD; however, the effects appear independent in this population.