Auriculotherapy for pain management: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: Side-effects of standard pain medications can limit their use. Therefore, nonpharmacologic pain relief techniques such as auriculotherapy may play an important role in pain management. Our aim was to conduct a systematic review and meta-analysis of studies evaluating auriculotherapy for pain management. DESIGN: MEDLINE,(®) ISI Web of Science, CINAHL, AMED, and Cochrane Library were searched through December 2008. Randomized trials comparing auriculotherapy to sham, placebo, or standard-of-care control were included that measured outcomes of pain or medication use and were published in English. Two (2) reviewers independently assessed trial eligibility, quality, and abstracted data to a standardized form. Standardized mean differences (SMD) were calculated for studies using a pain score or analgesic requirement as a primary outcome. RESULTS: Seventeen (17) studies met inclusion criteria (8 perioperative, 4 acute, and 5 chronic pain). Auriculotherapy was superior to controls for studies evaluating pain intensity (SMD, 1.56 [95% confidence interval (CI): 0.85, 2.26]; 8 studies). For perioperative pain, auriculotherapy reduced analgesic use (SMD, 0.54 [95% CI: 0.30, 0.77]; 5 studies). For acute pain and chronic pain, auriculotherapy reduced pain intensity (SMD for acute pain, 1.35 [95% CI: 0.08, 2.64], 2 studies; SMD for chronic pain, 1.84 [95% CI: 0.60, 3.07], 5 studies). Removal of poor quality studies did not alter the conclusions. Significant heterogeneity existed among studies of acute and chronic pain, but not perioperative pain. CONCLUSIONS: Auriculotherapy may be effective for the treatment of a variety of types of pain, especially postoperative pain. However, a more accurate estimate of the effect will require further large, well-designed trials.

Missing data in randomized clinical trials for weight loss: scope of the problem, state of the field, and performance of statistical methods.

BACKGROUND: Dropouts and missing data are nearly-ubiquitous in obesity randomized controlled trails, threatening validity and generalizability of conclusions. Herein, we meta-analytically evaluate the extent of missing data, the frequency with which various analytic methods are employed to accommodate dropouts, and the performance of multiple statistical methods. METHODOLOGY/PRINCIPAL FINDINGS: We searched PubMed and Cochrane databases (2000-2006) for articles published in English and manually searched bibliographic references. Articles of pharmaceutical randomized controlled trials with weight loss or weight gain prevention as major endpoints were included. Two authors independently reviewed each publication for inclusion. 121 articles met the inclusion criteria. Two authors independently extracted treatment, sample size, drop-out rates, study duration, and statistical method used to handle missing data from all articles and resolved disagreements by consensus. In the meta-analysis, drop-out rates were substantial with the survival (non-dropout) rates being approximated by an exponential decay curve (e(-lambdat)) where lambda was estimated to be .0088 (95% bootstrap confidence interval: .0076 to .0100) and t represents time in weeks. The estimated drop-out rate at 1 year was 37%. Most studies used last observation carried forward as the primary analytic method to handle missing data. We also obtained 12 raw obesity randomized controlled trial datasets for empirical analyses. Analyses of raw randomized controlled trial data suggested that both mixed models and multiple imputation performed well, but that multiple imputation may be more robust when missing data are extensive. CONCLUSION/SIGNIFICANCE: Our analysis offers an equation for predictions of dropout rates useful for future study planning. Our raw data analyses suggests that multiple imputation is better than other methods for handling missing data in obesity randomized controlled trials, followed closely by mixed models. We suggest these methods supplant last observation carried forward as the primary method of analysis.

What leads Indians to participate in clinical trials? A meta-analysis of qualitative studies.

BACKGROUND: With the globalization of clinical trials, large developing nations have substantially increased their participation in multi-site studies. This participation has raised ethical concerns, among them the fear that local customs, habits and culture are not respected while asking potential participants to take part in study. This knowledge gap is particularly noticeable among Indian subjects, since despite the large number of participants, little is known regarding what factors affect their willingness to participate in clinical trials. METHODS: We conducted a meta-analysis of all studies evaluating the factors and barriers, from the perspective of potential Indian participants, contributing to their participation in clinical trials. We searched both international as well as Indian-specific bibliographic databases, including Pubmed, Cochrane, Openjgate, MedInd, Scirus and Medknow, also performing hand searches and communicating with authors to obtain additional references. We enrolled studies dealing exclusively with the participation of Indians in clinical trials. Data extraction was conducted by three researchers, with disagreement being resolved by consensus. RESULTS: Six qualitative studies and one survey were found evaluating the main themes affecting the participation of Indian subjects. Themes included Personal health benefits, Altruism, Trust in physicians, Source of extra income, Detailed knowledge, Methods for motivating participants as factors favoring, while Mistrust on trial organizations, Concerns about efficacy and safety of trials, Psychological reasons, Trial burden, Loss of confidentiality, Dependency issues, Language as the barriers. CONCLUSION: We identified factors that facilitated and barriers that have negative implications on trial participation decisions in Indian subjects. Due consideration and weightage should be assigned to these factors while planning future trials in India.

So different, yet so similar: meta-analysis and policy modeling of willingness to participate in clinical trials among Brazilians and Indians.

BACKGROUND: With the global expansion of clinical trials and the expectations of the rise of the emerging economies known as BRICs (Brazil, Russia, India and China), the understanding of factors that affect the willingness to participate in clinical trials of patients from those countries assumes a central role in the future of health research. METHODS: We conducted a systematic review and meta-analysis (SRMA) of willingness to participate in clinical trials among Brazilian patients and then we compared it with Indian patients (with results of another SRMA previously conducted by our group) through a system dynamics model. RESULTS: Five studies were included in the SRMA of Brazilian patients. Our main findings are 1) the major motivation for Brazilian patients to participate in clinical trials is altruism, 2) monetary reimbursement is the least important factor motivating Brazilian patients, 3) the major barrier for Brazilian patients to not participate in clinical trials is the fear of side effects, and 4) Brazilian patients are more likely willing to participate in clinical trials than Indians. CONCLUSION: Our study provides important insights for investigators and sponsors for planning trials in Brazil (and India) in the future. Ignoring these results may lead to unnecessary fund/time spending. More studies are needed to validate our results and for better understanding of this poorly studied theme.

Economic return of clinical trials performed under the pediatric exclusivity program.

CONTEXT: In 1997, Congress authorized the US Food and Drug Administration (FDA) to grant 6-month extensions of marketing rights through the Pediatric Exclusivity Program if industry sponsors complete FDA-requested pediatric trials. The program has been praised for creating incentives for studies in children and has been criticized as a "windfall" to the innovator drug industry. This critique has been a substantial part of congressional debate on the program, which is due to expire in 2007. OBJECTIVE: To quantify the economic return to industry for completing pediatric exclusivity trials. DESIGN AND SETTING: A cohort study of programs conducted for pediatric exclusivity. Nine drugs that were granted pediatric exclusivity were selected. From the final study reports submitted to the FDA (2002-2004), key elements of the clinical trial design and study operations were obtained, and the cost of performing each study was estimated and converted into estimates of after-tax cash outflows. Three-year market sales were obtained and converted into estimates of after-tax cash inflows based on 6 months of additional market protection. Net economic return (cash inflows minus outflows) and net return-to-costs ratio (net economic return divided by cash outflows) for each product were then calculated. MAIN OUTCOME MEASURES: Net economic return and net return-to-cost ratio. RESULTS: The indications studied reflect a broad representation of the program: asthma, tumors, attention-deficit/hyperactivity disorder, hypertension, depression/generalized anxiety disorder, diabetes mellitus, gastroesophageal reflux, bacterial infection, and bone mineralization. The distribution of net economic return for 6 months of exclusivity varied substantially among products (net economic return ranged from -$8.9 million to $507.9 million and net return-to-cost ratio ranged from -0.68 to 73.63). CONCLUSIONS: The economic return for pediatric exclusivity is variable. As an incentive to complete much-needed clinical trials in children, pediatric exclusivity can generate lucrative returns or produce more modest returns on investment.

In vivo guidance and assessment of liver radio-frequency ablation with acoustic radiation force elastography.

The initial results from clinical trials investigating the utility of acoustic radiation force impulse (ARFI) imaging for use with radio-frequency ablation (RFA) procedures in the liver are presented. To date, data have been collected from 6 RFA procedures in 5 unique patients. Large displacement contrast was observed in ARFI images of both pre-ablation malignancies (mean 7.5 dB, range 5.7-11.9 dB) and post-ablation thermal lesions (mean 6.2 dB, range 5.1-7.5 dB). In general, ARFI images provided superior boundary definition of structures relative to the use of conventional sonography alone. Although further investigations are required, initial results are encouraging and demonstrate the clinical promise of the ARFI method for use in many stages of RFA procedures.

Improving mental health among people living with HIV: a review of intervention trials in low- and middle-income countries.

People living with HIV (PLWH) experience greater psychological distress than the general population. Evidence from high-incomes countries suggests that psychological interventions for PLWH can improve mental health symptoms, quality of life, and HIV care engagement. However, little is known about the effectiveness of mental health interventions for PLWH in low and middle-income countries (LMICs), where the large majority of PLWH reside. This systematized review aims to synthesize findings from mental health intervention trials with PLWH in LMICs to inform the delivery of mental health services in these settings. A systematic search strategy was undertaken to identify peer-reviewed published papers of intervention trials addressing negative psychological states or disorders (e.g., depression, anxiety) among PLWH in LMIC settings. Search results were assessed against pre-established inclusion and exclusion criteria. Data from papers meeting criteria were extracted for synthesis. Twenty-six papers, published between 2000 and 2014, describing 22 unique interventions were identified. Trials were implemented in sub-Saharan Africa (n=13), Asia (n=7), and the Middle East (n=2), and addressed mental health using a variety of approaches, including cognitive-behavioral (n=18), family-level (n=2), and pharmacological (n=2) treatments. Four randomized controlled trials reported significant intervention effects in mental health outcomes, and eleven preliminary studies demonstrated promising findings. Among the limited mental health intervention trials with PLWH in LMICs, few demonstrated efficacy. Mental health interventions for PLWH in LMICs must be further developed and adapted for resource-limited settings to improve effectiveness.

Using electronic health record data for substance use Screening, Brief Intervention, and Referral to Treatment among adults with type 2 diabetes: Design of a National Drug Abuse Treatment Clinical Trials Network study.

BACKGROUND: The Affordable Care Act encourages healthcare systems to integrate behavioral and medical healthcare, as well as to employ electronic health records (EHRs) for health information exchange and quality improvement. Pragmatic research paradigms that employ EHRs in research are needed to produce clinical evidence in real-world medical settings for informing learning healthcare systems. Adults with comorbid diabetes and substance use disorders (SUDs) tend to use costly inpatient treatments; however, there is a lack of empirical data on implementing behavioral healthcare to reduce health risk in adults with high-risk diabetes. Given the complexity of high-risk patients' medical problems and the cost of conducting randomized trials, a feasibility project is warranted to guide practical study designs. METHODS: We describe the study design, which explores the feasibility of implementing substance use Screening, Brief Intervention, and Referral to Treatment (SBIRT) among adults with high-risk type 2 diabetes mellitus (T2DM) within a home-based primary care setting. Our study includes the development of an integrated EHR datamart to identify eligible patients and collect diabetes healthcare data, and the use of a geographic health information system to understand the social context in patients' communities. Analysis will examine recruitment, proportion of patients receiving brief intervention and/or referrals, substance use, SUD treatment use, diabetes outcomes, and retention. DISCUSSION: By capitalizing on an existing T2DM project that uses home-based primary care, our study results will provide timely clinical information to inform the designs and implementation of future SBIRT studies among adults with multiple medical conditions.

Gender and racial/ethnic differences in addiction severity, HIV risk, and quality of life among adults in opioid detoxification: results from the National Drug Abuse Treatment Clinical Trials Network.

PURPOSE: Detoxification often serves as an initial contact for treatment and represents an opportunity for engaging patients in aftercare to prevent relapse. However, there is limited information concerning clinical profiles of individuals seeking detoxification, and the opportunity to engage patients in detoxification for aftercare often is missed. This study examined clinical profiles of a geographically diverse sample of opioid-dependent adults in detoxification to discern the treatment needs of a growing number of women and whites with opioid addiction and to inform interventions aimed at improving use of aftercare or rehabilitation. METHODS: The sample included 343 opioid-dependent patients enrolled in two national multi-site studies of the National Drug Abuse Treatment Clinical Trials Network (CTN001-002). Patients were recruited from 12 addiction treatment programs across the nation. Gender and racial/ethnic differences in addiction severity, human immunodeficiency virus (HIV) risk, and quality of life were examined. RESULTS: Women and whites were more likely than men and African Americans to have greater psychiatric and family/social relationship problems and report poorer health-related quality of life and functioning. Whites and Hispanics exhibited higher levels of total HIV risk scores and risky injection drug use scores than African Americans, and Hispanics showed a higher level of unprotected sexual behaviors than whites. African Americans were more likely than whites to use heroin and cocaine and to have more severe alcohol and employment problems. CONCLUSIONS: Women and whites show more psychopathology than men and African Americans. These results highlight the need to monitor an increased trend of opioid addiction among women and whites and to develop effective combined psychosocial and pharmacologic treatments to meet the diverse needs of the expanding opioid-abusing population. Elevated levels of HIV risk behaviors among Hispanics and whites also warrant more research to delineate mechanisms and to reduce their risky behaviors.

Impact of Funding Source on Clinical Trial Results Including Cardiovascular Outcome Trials.

Previous authors have suggested a higher likelihood for industry-sponsored (IS) studies to have positive outcomes than non-IS studies, though the influence of publication bias was believed to be a likely confounder. We attempted to control for the latter using a prepublication database to compare the primary outcome of recent trials based on sponsorship. We used the "advanced search" feature in the clinicaltrials.gov website to identify recently completed phase III studies involving the implementation of a pharmaceutical agent or device for which primary data were available. Studies were categorized as either National Institutes of Health (NIH) sponsored or IS. Results were labeled "favorable" if the results favored the intervention under investigation or "unfavorable" if the intervention fared worse than standard medical treatment. We also performed an independent literature search to identify the cardiovascular trials as a case example and again categorized them into IS versus NIH sponsored. A total of 226 studies sponsored by NIH were found. When these were compared with the latest 226 IS studies, it was found that IS studies were almost 4 times more likely to report a positive outcome (odds ratio [OR] 3.90, 95% confidence interval [CI] 2.6087 to 5.9680, p <0.0001). As a case example of a specialty, we also identified 25 NIH-sponsored and 215 IS cardiovascular trials, with most focusing on hypertension therapy (31.6%) and anticoagulation (17.9%). IS studies were 7 times more likely to report favorable outcomes (OR 7.54, 95% CI 2.19 to 25.94, p = 0.0014). They were also considerably less likely to report unfavorable outcomes (OR 0.11, 95% CI 0.04 to 0.26, p <0.0001). In conclusion, the outcomes of large clinical studies especially cardiovascular differ considerably on the basis of their funding source, and publication bias appears to have limited influence on these findings.

Conflicts of Interest and Outcomes of Cardiovascular Trials.

Conflicts of interests have long been recognized as potential sources of influence in the conduct and reporting of clinical trials. This controversy was again rekindled after the publication of the latest statin guidelines and a series of studies regarding competing interests in leading medical journals. We investigate the association between declared author conflicts and the outcomes of large cardiovascular trials. We searched the Medline (PubMed) database to identify "phase 2" and "phase 3" clinical trials using the search term "cardiovascular" over the past decade using "10 years" as the filter. We perceived the competing interest as present regardless of the nature such as consulting fees, honoraria, travel imbursements, stock holding, and employment. Of the 699 titles retrieved, 114 studies met the inclusion criteria. Nearly 80% of studies had at least a single author with competing interests. The 114 studies had a total of 1,433 investigators, of which 725 had declared conflicts of interests (50.6%). A total of 66 studies (58%) had half or >50 percent of investigators who had some conflicts of interests. Of these studies, 54 studies had favorable outcomes and only 12 had unfavorable outcomes (p <0.001). Among the type of competing interests, consulting or personal fees was the most common present in 58 investigators (51%). This was followed by research grants present in 55 the researchers (48%). Among 25 (22%) studies, at least one investigator reported stakes in the industry, of which only 2 studies had unfavorable outcomes for the intervention being investigated. Just 1 of the 25 clinical trials with a sample size of >1,000 had no investigators with competing interests. In conclusion, authors conflicts are associated with favorable outcomes in cardiovascular outcome trials.

Utility of a molecular prescreening program in advanced colorectal cancer for enrollment on biomarker-selected clinical trials.

BACKGROUND: Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation, but the factors that determine clinical trial enrollment following a molecular prescreening program have not been assessed. PATIENTS AND METHODS: Patients with 5-fluorouracil-refractory metastatic colorectal cancer at the MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion phase I or II clinical trials with a therapy targeted to an aberration detected in the patient, based on testing by immunohistochemistry, targeted gene sequencing panels, and CpG island methylation phenotype assays. RESULTS: Between August 2010 and December 2013, 484 patients were enrolled, 458 (95%) had a biomarker result, and 157 (32%) were enrolled on a clinical trial (92 on biomarker-selected and 65 on nonbiomarker selected). Of the 458 patients with a biomarker result, enrollment on biomarker-selected clinical trials was ninefold higher for predefined ATTACC-companion clinical trials as opposed to nonpredefined biomarker-selected clinical trials, 17.9% versus 2%, P < 0.001. Factors that correlated positively with trial enrollment in multivariate analysis were higher performance status, older age, lack of standard of care therapy, established patient at MD Anderson, and the presence of an eligible biomarker for an ATTACC-companion study. Early molecular screening did result in a higher rate of patients with remaining standard of care therapy enrolling on ATTACC-companion clinical trials, 45.1%, in contrast to nonpredefined clinical trials, 22.7%; odds ratio 3.1, P = 0.002. CONCLUSIONS: Though early molecular prescreening for predefined clinical trials resulted in an increase rate of trial enrollment of nonrefractory patients, the majority of patients enrolled on clinical trials were refractory to standard of care therapy. Within molecular prescreening programs, tailoring screening for preidentified and open clinical trials, temporally linking screening to treatment and optimizing both patient and physician engagement are efforts likely to improve enrollment on biomarker-selected clinical trials. CLINICAL TRIALS NUMBER: The study NCT number is NCT01196130.