Pragmatic guidance for embedding pragmatic clinical trials in health plans: Large simple trials aren't so simple.

BACKGROUND: There are unique opportunities related to the design and conduct of pragmatic trials embedded in health insurance plans, which have longitudinal data on member/patient demographics, dates of coverage, and reimbursed medical care, including prescription drug dispensings, vaccine administrations, behavioral healthcare encounters, and some laboratory results. Such trials can be large and efficient, using these data to identify trial-eligible patients and to ascertain outcomes. METHODS: We use our experience primarily with the National Institutes of Health Pragmatic Trials Collaboratory Distributed Research Network, which comprises health plans that participate in the US Food & Drug Administration's Sentinel System, to describe lessons learned from the conduct and planning of embedded pragmatic trials. RESULTS: Information is available for research on more than 75 million people with commercial or Medicare Advantage health plans. We describe three studies that have used or plan to use the Network, as well as a single health plan study, from which we glean our lessons learned. CONCLUSIONS: Studies that are conducted in health plans provide much-needed evidence to drive clinically meaningful changes in care. However, there are many unique aspects of these trials that must be considered in the planning, implementation, and analytic phases. The type of trial best suited for studies embedded in health plans will be those that require large sample sizes, simple interventions that could be disseminated through health plans, and where data available to the health plan can be leveraged. These trials hold potential for substantial long-term impact on our ability to generate evidence to improve care and population health.

A Comparative Study to Evaluate the Efficacy and Cost of Rituximab versus Dexamethasone Cyclophosphamide Pulse in Patients of Pemphigus Vulgaris.

INTRODUCTION: Rituximab is slowly getting recognized as a promising steroid-sparing agent in the treatment of moderate to severe cases of pemphigus vulgaris (PV). We evaluated and compared the effectiveness, safety, and cost of therapy of rituximab versus dexamethasone cyclophosphamide pulse (DCP) in Indian patients with PV. MATERIALS AND METHODS: It is a retrospective data analysis, from the Immunobullous disease clinic in a tertiary centre of eastern India, of management of PV. In our institute we use either rituximab or DCP for the management of moderate to severe cases of PV, depending on that we retrospectively divided the treated cases of PV in two groups. Patients who were treated with rheumatoid arthritis (RA) protocol of rituximab were considered to be group 1. Patients who were treated with DCP were included in group 2. Response was assessed by pemphigus area, and activity score (PAAS), Dermatology life quality index (DLQI); photographic documentation, and blood parameters were monitored. RESULTS: Both groups showed significant improvement in PAAS and DLQI, the improvement was faster and well sustained in the rituximab group. In terms of safety and development of new vesicles, rituximab had a better profile with only 1 patient having adverse effects and none with new vesicles as compared to DCP (3 had adverse effects and 2 developed new vesicles). CONCLUSIONS: Rituximab offers the advantage of early and prolonged remission, lesser adverse effects, better effectiveness, less risk of relapses, faster improvement of PAAS, and DLQI. Though rituximab is an expensive drug, but on evaluating the cost of whole therapy, it was seen that rituximab infusions are actually cheaper compared to DCP pulse. We suggest, rituximab can be used as the first-line of therapy for pemphigus vulgaris in the Indian context.

Association of antidiabetic therapies with lower extremity amputation, mortality and healthcare cost from a nationwide retrospective cohort study in Taiwan.

We compared risks of clinical outcomes, mortality and healthcare costs among new users of different classes of anti-diabetic medications. This is a population-based, retrospective, new-user design cohort study using the Taiwan National Health Insurance Database between May 2, 2015 and September 30, 2017. An individual was assigned to a medication group based on the first anti-diabetic prescription on or after May 1, 2016: SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 agonists or older agents (metformin, etc.). Clinical outcomes included lower extremity amputation, peripheral vascular disease, critical limb ischemia, osteomyelitis, and ulcer. We built three Cox proportional hazards models for clinical outcomes and mortality, and three regression models with a log-link function and gamma distribution for healthcare costs, all with propensity-score weighting and covariates. We identified 1,222,436 eligible individuals. After adjustment, new users of SGLT-2 inhibitors were associated with 73% lower mortality compared to those of DPP-4 inhibitors or users of older agents, while 36% lower total costs against those of GLP-1 agonists. However, there was no statistically significant difference in the risk of lower extremity amputation across medication groups. Our study suggested that SGLT-2 inhibitors is associated with lower mortality compared to DPP 4 inhibitors and lower costs compared to GLP-1 agonists.

Positive deviance approaches to improving vaccination coverage rates within healthcare systems: a systematic review.

Aim: Our objective was to systematically review the use of the positive deviance approach to identify strategies to improve vaccination coverage rates. Materials & methods: We searched English language articles in Medline, Embase, Cochrane Library, CINAHL and PsycINFO without any date restrictions on 4 October 2017. We compiled a list of all strategies and evaluated the quality of these studies using the QATSDD tool. Results: After a review of 241 citations, we included eight studies. These studies focused on a wide variety of vaccines and settings. Core strategies that support vaccine uptake include the importance of tailoring and targeting in both messaging and delivery of vaccines and tracking delivery of vaccines. Patient and provider education, reminders, feedback loops, community collaborations, immunization registries and use of a medical home were also identified as other strategies. Conclusion: Our findings highlight several useful core strategies, which can be used to promote vaccination coverage. PROSPERO: CRD42017078221.

A comparison of two algorithms to identify sudden cardiac deaths in computerized databases.

PURPOSE: Two previously validated algorithms to identify sudden cardiac death using administrative data showed high positive predictive value. We evaluated the agreement between the algorithms using data from a common source population. METHODS: We conducted a cross-sectional study to assess the percent agreement between deaths identified by two sudden cardiac death algorithms using Tennessee Medicaid and death certificate data from 2007 through 2014. The source population included all deceased patients aged 18 to 64 years with Medicaid enrollment in the 6 months prior to death. To identify sudden cardiac deaths, algorithm 1 used only hospital/emergency department (ED) claims from encounters at the time of death, and algorithm 2 required death certificates and used claims data for specific exclusion criteria. RESULTS: We identified 34 107 deaths in the source population over the study period. The two algorithms identified 4372 potential sudden cardiac deaths: Algorithm 1 identified 3117 (71.3%) and algorithm 2 identified 1715 (39.2%), with 460 (10.5%) deaths identified by both algorithms. Of the deaths identified by algorithm 1, 1943 (62.3%) had an underlying cause of death not specified in algorithm 2. Of the deaths identified by algorithm 2, 1053 (61.4%) had no record of a hospital or ED encounter at the time of death, and 202 (11.8%) had a discharge diagnosis code not specified in algorithm 1. CONCLUSIONS: We found low agreement between the two algorithms for identification of sudden cardiac deaths because of differences in sudden cardiac death definitions and data sources.

Bone stress injuries in male distance runners: higher modified Female Athlete Triad Cumulative Risk Assessment scores predict increased rates of injury.

OBJECTIVES: Bone stress injuries (BSI) are common in runners of both sexes. The purpose of this study was to determine if a modified Female Athlete Triad Cumulative Risk Assessment tool would predict BSI in male distance runners. METHODS: 156 male runners at two collegiate programmes were studied using mixed retrospective and prospective design for a total of 7 years. Point values were assigned using risk assessment categories including low energy availability, low body mass index (BMI), low bone mineral density (BMD) and prior BSI. The outcome was subsequent development of BSI. Statistical models used a mixed effects Poisson regression model with p<0.05 as threshold for significance. Two regression analyses were performed: (1) baseline risk factors as the independent variable; and (2) annual change in risk factors (longitudinal data) as the independent variable. RESULTS: 42/156 runners (27%) sustained 61 BSIs over an average 1.9 years of follow-up. In the baseline risk factor model, each 1 point increase in prior BSI score was associated with a 57% increased risk for prospective BSI (p=0.0042) and each 1 point increase in cumulative risk score was associated with a 37% increase in prospective BSI risk (p=0.0079). In the longitudinal model, each 1 point increase in cumulative risk score was associated with a 27% increase in prospective BSI risk (p=0.05). BMI (rate ratio (RR)=1.91, p=0.11) and BMD (RR=1.58, p=0.19) risk scores were not associated with BSI. CONCLUSION: A modified cumulative risk assessment tool may help identify male runners at elevated risk for BSI. Identifying risk factors may guide treatment and prevention strategies.

Determining the scope of attacks on health in four governorates of Syria in 2016: Results of a field surveillance program.

BACKGROUND: Violent attacks on and interferences with hospitals, ambulances, health workers, and patients during conflict destroy vital health services during a time when they are most needed and undermine the long-term capacity of the health system. In Syria, such attacks have been frequent and intense and represent grave violations of the Geneva Conventions, but the number reported has varied considerably. A systematic mechanism to document these attacks could assist in designing more protection strategies and play a critical role in influencing policy, promoting justice, and addressing the health needs of the population. METHODS AND FINDINGS: We developed a mobile data collection questionnaire to collect data on incidents of attacks on healthcare directly from the field. Data collectors from the Syrian American Medical Society (SAMS), using the tool or a text messaging system, recorded information on incidents across four of Syria's northern governorates (Aleppo, Idleb, Hama, and Homs) from January 1, 2016, to December 31, 2016. SAMS recorded a total of 200 attacks on healthcare in 2016, 102 of them using the mobile data collection tool. Direct attacks on health facilities comprised the majority of attacks recorded (88.0%; n = 176). One hundred and twelve healthcare staff and 185 patients were killed in these incidents. Thirty-five percent of the facilities were attacked more than once over the data collection period; hospitals were significantly more likely to be attacked more than once compared to clinics and other types of healthcare facilities. Aerial bombs were used in the overwhelming majority of cases (91.5%). We also compared the SAMS data to a separate database developed by Physicians for Human Rights (PHR) based on media reports and matched the incidents to compare the results from the two methods (this analysis was limited to incidents at health facilities). Among 90 relevant incidents verified by PHR and 177 by SAMS, there were 60 that could be matched to each other, highlighting the differences in results from the two methods. This study is limited by the complexities of data collection in a conflict setting, only partial use of the standardized reporting tool, and the fact that limited accessibility of some health facilities and workers and may be biased towards the reporting of attacks on larger or more visible health facilities. CONCLUSIONS: The use of field data collectors and use of consistent definitions can play an important role in the tracking incidents of attacks on health services. A mobile systematic data collection tool can complement other methods for tracking incidents of attacks on healthcare and ensure the collection of detailed information about each attack that may assist in better advocacy, programs, and accountability but can be practically challenging. Comparing attacks between SAMS and PHR suggests that there may have been significantly more attacks than previously captured by any one methodology. This scale of attacks suggests that targeting of healthcare in Syria is systematic and highlights the failure of condemnation by the international community and medical groups working in Syria of such attacks to stop them.

Evidence selection for a prescription drug's benefit-harm assessment: challenges and recommendations.

OBJECTIVES: To describe challenges and make recommendations for researchers in how they select evidence to quantitatively assess a prescription drug's benefits and harms. STUDY DESIGN AND SETTING: These challenges and recommendations are based on our recent experience conducting a benefit-harm assessment for the prescription drug roflumilast. We considered the selection of evidence to quantify (1) the drug's treatment effects in patients, (2) the patient population's baseline risks for beneficial and harmful outcomes without treatment, and (3) the patient population's preferences for these beneficial effects and harms. These are fundamental steps for most benefit-harm assessment methods. RESULTS: We identify critical issues in selecting evidence for each of these steps. We justify in particular the need to incorporate (1) clinical trials for the drug's specific treatment effect; (2) observational studies with the most valid, precise, and applicable effect estimates for the baseline risk; and (3) flexible weighting approaches for balancing the drug benefits and harms. CONCLUSION: We identify challenges and make recommendations for selecting evidence at the critical steps in a prescription drug's benefit-harm assessment. Our findings should assist other researchers conducting these assessments for prescription drugs, which could help regulators, medical professionals, and patients make better decisions about prescription drug use.

Psychometric properties and reliability of the Assessment Screen to Identify Survivors Toolkit for Gender Based Violence (ASIST-GBV): results from humanitarian settings in Ethiopia and Colombia.

BACKGROUND: Refugees and internally displaced persons who are affected by armed-conflict are at increased vulnerability to some forms of sexual violence or other types of gender-based violence. A validated, brief and easy-to-administer screening tool will help service providers identify GBV survivors and refer them to appropriate GBV services. To date, no such GBV screening tool exists. We developed the 7-item ASIST-GBV screening tool from qualitative research that included individual interviews and focus groups with GBV refugee and IDP survivors. This study presents the psychometric properties of the ASIST-GBV with female refugees living in Ethiopia and IDPs in Colombia. METHODS: Several strategies were used to validate ASIST-GBV, including a 3 month implementation to validate the brief screening tool with women/girls seeking health services, aged ≥15 years in Ethiopia (N = 487) and female IDPs aged ≥ 18 years in Colombia (N = 511). RESULTS: High proportions of women screened positive for past-year GBV according to the ASIST-GBV: 50.6 % in Ethiopia and 63.4 % in Colombia. The factor analysis identified a single dimension, meaning that all items loaded on the single factor. Cronbach's α = 0.77. A 2-parameter logistic IRT model was used for estimating the precision and discriminating power of each item. Item difficulty varied across the continuum of GBV experiences in the following order (lowest to highest): threats of violence (0.690), physical violence (1.28), forced sex (2.49), coercive sex for survival (2.25), forced marriage (3.51), and forced pregnancy (6.33). Discrimination results showed that forced pregnancy was the item with the strongest ability to discriminate between different levels of GBV. Physical violence and forced sex also have higher levels of discrimination with threats of violence discriminating among women at the low end of the GBV continuum and coercive sex for survival among women at the mid-range of the continuum. CONCLUSION: The findings demonstrate that the ASIST-GBV has strong psychometric properties and good reliability. The tool can be used to screen and identify female GBV survivors confidentially and efficiently among IDPs in Colombia and refugees in Ethiopia. Early identification of GBV survivors can enable safety planning, early referral for treatment, and psychosocial support to prevent long-term harmful consequence of GBV.

Social isolation and health in widowhood: A qualitative study of Nepali widows' experiences.

Little research exists on social isolation and health among widows despite their marginalization in South Asia. Using a conceptual framework that delineates distinct forms of social support, our results provide a preliminary analysis of the role social support plays in the well-being of Nepali widows. Between 2011 and 2012, we conducted 42 in-depth interviews in the Kathmandu valley and Surkhet district. Low social support was a common theme, principally lacking in the domains of emotional and instrumental support and was described as increasing women's vulnerability to mistreatment and economic insecurity. Policies and programs that foster these types of support may have positive effects on widows' well-being.

Developments in Surge Research Priorities: A Systematic Review of the Literature Following the Academic Emergency Medicine Consensus Conference, 2007-2015.

OBJECTIVES: In 2006, Academic Emergency Medicine (AEM) published a special issue summarizing the proceedings of the AEM consensus conference on the "Science of Surge." One major goal of the conference was to establish research priorities in the field of "disasters" surge. For this review, we wished to determine the progress toward the conference's identified research priorities: 1) defining criteria and methods for allocation of scarce resources, 2) identifying effective triage protocols, 3) determining decision-makers and means to evaluate response efficacy, 4) developing communication and information sharing strategies, and 5) identifying methods for evaluating workforce needs. METHODS: Specific criteria were developed in conjunction with library search experts. PubMed, Embase, Web of Science, Scopus, and the Cochrane Library databases were queried for peer-reviewed articles from 2007 to 2015 addressing scientific advances related to the above five research priorities identified by AEM consensus conference. Abstracts and foreign language articles were excluded. Only articles with quantitative data on predefined outcomes were included; consensus panel recommendations on the above priorities were also included for the purposes of this review. Included study designs were randomized controlled trials, prospective, retrospective, qualitative (consensus panel), observational, cohort, case-control, or controlled before-and-after studies. Quality assessment was performed using a standardized tool for quantitative studies. RESULTS: Of the 2,484 unique articles identified by the search strategy, 313 articles appeared to be related to disaster surge. Following detailed text review, 50 articles with quantitative data and 11 concept papers (consensus conference recommendations) addressed at least one AEM consensus conference surge research priority. Outcomes included validation of the benchmark of 500 beds/million of population for disaster surge capacity, effectiveness of simulation- and Internet-based tools for forecasting of hospital and regional demand during disasters, effectiveness of reverse triage approaches, development of new disaster surge metrics, validation of mass critical care approaches (altered standards of care), use of telemedicine, and predictions of optimal hospital staffing levels for disaster surge events. Simulation tools appeared to provide some of the highest quality research. CONCLUSION: Disaster simulation studies have arguably revolutionized the study of disaster surge in the intervening years since the 2006 AEM Science of Surge conference, helping to validate some previously known disaster surge benchmarks and to generate new surge metrics. Use of reverse triage approaches and altered standards of care, as well as Internet-based tools such as Google Flu Trends, have also proven effective. However, there remains significant work to be done toward standardizing research methodologies and outcomes, as well as validating disaster surge metrics.

Adherence to a Novel Oral Anticoagulant Among Patients with Atrial Fibrillation.

BACKGROUND: Dabigatran is a direct thrombin inhibitor approved by the FDA in October 2010 for the treatment of nonvalvular atrial fibrillation. Little is known regarding patient adherence to this therapy. OBJECTIVE: To examine adherence and persistence to dabigatran among adults with atrial fibrillation. METHODS: We used IMS Health's LifeLink Health Plan Claims Database from 2010 to 2012 to identify patients with atrial fibrillation who were new users of dabigatran. We derived adherence and persistence for continuously enrolled patients at 6 months, 9 months, and 12 months of follow-up. We measured adherence using the medication possession ratio (MPR), defined as individuals with MPRs of 0.80 or greater as adherent, and examined persistence by identifying individuals with gaps in drug possession of 60 days or greater. RESULTS: Of 5,951 adults with atrial fibrillation who were new users of dabigatran, 49% had prevalent atrial fibrillation and at least 6 months of continuous follow-up. Of these, 89% used dabigatran as the only oral anticoagulant, whereas the remainder filled prescriptions for at least 1 other oral anticoagulant during the follow-up period. Among those using dabigatran alone (n = 2,713), the mean MPR was 0.73 (standard error = 0.30), 41% were nonadherent with therapy, and 32% had gaps of 60 days or greater. Among those observed for 9 (or 12) months who used dabigatran alone, rates of nonadherence were 47% (49%), whereas 48% (49%) discontinued therapy during follow-up. Rates of adherence and persistence were similar for patients with incident atrial fibrillation. CONCLUSIONS: Nonadherence to dabigatran was common among patients with atrial fibrillation. Future studies are needed to understand the reasons for nonadherence.

Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study.

OBJECTIVE: To determine the real world risk of gastrointestinal bleeding associated with the use of the novel oral anticoagulants dabigatran and rivaroxaban compared with warfarin. DESIGN: Retrospective, propensity matched cohort study. SETTING: Optum Labs Data Warehouse, a large database including administrative claims data on privately insured and Medicare Advantage enrollees. PARTICIPANTS: New users of dabigatran, rivaroxaban, and warfarin from 1 November 2010 to 30 September 2013. MAIN OUTCOME MEASURES: Incidence rates (events/100 patient years) and propensity score matched Cox proportional hazards models were used to estimate rates of total gastrointestinal bleeds, upper gastrointestinal bleeds, and lower gastrointestinal bleeds for the novel oral anticoagulants compared with warfarin in patients with and without atrial fibrillation. Heterogeneity of treatment effect related to age was examined using a marginal effects model. RESULTS: The incidence of gastrointestinal bleeding associated with dabigatran was 2.29 (95% confidence interval 1.88 to 2.79) per 100 patient years and that associated with warfarin was 2.87 (2.41 to 3.41) per 100 patient years in patients with atrial fibrillation. In non-atrial fibrillation patients, the incidence of gastrointestinal bleeding was 4.10 (2.47 to 6.80) per 100 patient years with dabigatran and 3.71 (2.16 to 6.40) per 100 patient years with warfarin. With rivaroxaban, 2.84 (2.30 to 3.52) gastrointestinal bleeding events per 100 patient years occurred in atrial fibrillation patients (warfarin 3.06 (2.49 to 3.77)/100 patient years) and 1.66 (1.23 to 2.24) per 100 patient years in non-atrial fibrillation patients (warfarin 1.57 (1.25 to 1.99)/100 patient years). In propensity score matched models, the risk of gastrointestinal bleeding with novel oral anticoagulants was similar to that with warfarin in atrial fibrillation patients (dabigatran v warfarin, hazard ratio 0.79 (0.61 to 1.03); rivaroxaban v warfarin, 0.93 (0.69 to 1.25)) and in non-AF patients (dabigatran v warfarin, hazard ratio 1.14 (0.54 to 2.39); rivaroxaban v warfarin, 0.89 (0.60 to 1.32)). The risk of gastrointestinal bleeding increased after age 65, such that by age 76 the risk exceeded that with warfarin among atrial fibrillation patients taking dabigatran (hazard ratio 2.49 (1.61 to 3.83)) and patients with and without atrial fibrillation taking rivaroxaban (2.91 (1.65 to 4.81) and 4.58 (2.40 to 8.72), respectively). CONCLUSIONS: The risk of gastrointestinal bleeding related to novel oral anticoagulants was similar to that for warfarin. Caution should be used when prescribing novel oral anticoagulants to older people, particularly those over 75 years of age.

Systematic assessment of benefits and risks: study protocol for a multi-criteria decision analysis using the Analytic Hierarchy Process for comparative effectiveness research.

BACKGROUND: Regulatory decision-making involves assessment of risks and benefits of medications at the time of approval or when relevant safety concerns arise with a medication. The Analytic Hierarchy Process (AHP) facilitates decision-making in complex situations involving tradeoffs by considering risks and benefits of alternatives. The AHP allows a more structured method of synthesizing and understanding evidence in the context of importance assigned to outcomes. Our objective is to evaluate the use of an AHP in a simulated committee setting selecting oral medications for type 2 diabetes.  METHODS: This study protocol describes the AHP in five sequential steps using a small group of diabetes experts representing various clinical disciplines. The first step will involve defining the goal of the decision and developing the AHP model. In the next step, we will collect information about how well alternatives are expected to fulfill the decision criteria. In the third step, we will compare the ability of the alternatives to fulfill the criteria and judge the importance of eight criteria relative to the decision goal of the optimal medication choice for type 2 diabetes. We will use pairwise comparisons to sequentially compare the pairs of alternative options regarding their ability to fulfill the criteria. In the fourth step, the scales created in the third step will be combined to create a summary score indicating how well the alternatives met the decision goal. The resulting scores will be expressed as percentages and will indicate the alternative medications' relative abilities to fulfill the decision goal. The fifth step will consist of sensitivity analyses to explore the effects of changing the estimates. We will also conduct a cognitive interview and process evaluation.  DISCUSSION: Multi-criteria decision analysis using the AHP will aid, support and enhance the ability of decision makers to make evidence-based informed decisions consistent with their values and preferences.

A framework for organizing and selecting quantitative approaches for benefit-harm assessment.

BACKGROUND: Several quantitative approaches for benefit-harm assessment of health care interventions exist but it is unclear how the approaches differ. Our aim was to review existing quantitative approaches for benefit-harm assessment and to develop an organizing framework that clarifies differences and aids selection of quantitative approaches for a particular benefit-harm assessment. METHODS: We performed a review of the literature to identify quantitative approaches for benefit-harm assessment. Our team, consisting of clinicians, epidemiologists, and statisticians, discussed the approaches and identified their key characteristics. We developed a framework that helps investigators select quantitative approaches for benefit-harm assessment that are appropriate for a particular decisionmaking context. RESULTS: Our framework for selecting quantitative approaches requires a concise definition of the treatment comparison and population of interest, identification of key benefit and harm outcomes, and determination of the need for a measure that puts all outcomes on a single scale (which we call a benefit and harm comparison metric). We identified 16 quantitative approaches for benefit-harm assessment. These approaches can be categorized into those that consider single or multiple key benefit and harm outcomes, and those that use a benefit-harm comparison metric or not. Most approaches use aggregate data and can be used in the context of single studies or systematic reviews. Although the majority of approaches provides a benefit and harm comparison metric, only four approaches provide measures of uncertainty around the benefit and harm comparison metric (such as a 95 percent confidence interval). None of the approaches considers the actual joint distribution of benefit and harm outcomes, but one approach considers competing risks when calculating profile-specific event rates. Nine approaches explicitly allow incorporating patient preferences. CONCLUSION: The choice of quantitative approaches depends on the specific question and goal of the benefit-harm assessment as well as on the nature and availability of data. In some situations, investigators may identify only one appropriate approach. In situations where the question and available data justify more than one approach, investigators may want to use multiple approaches and compare the consistency of results. When more evidence on relative advantages of approaches accumulates from such comparisons, it will be possible to make more specific recommendations on the choice of approaches.

Drug safety assessment in clinical trials: methodological challenges and opportunities.

Randomized controlled trials are the principal means of establishing the efficacy of drugs. However pre-marketing trials are limited in size and duration and exclude high-risk populations. They have limited statistical power to detect rare but potentially serious adverse events in real-world patients. We summarize the principal methodological challenges in the reporting, analysis and interpretation of safety data in clinical trials using recent examples from systematic reviews. These challenges include the lack of an evidentiary gold standard, the limited statistical power of randomized controlled trials and resulting type 2 error, the lack of adequate ascertainment of adverse events and limited generalizability of trials that exclude high risk patients. We discuss potential solutions to these challenges. Evaluation of drug safety requires careful examination of data from heterogeneous sources. Meta-analyses of drug safety should include appropriate statistical methods and assess the optimal information size to avoid type 2 errors. They should evaluate outcome reporting biases and missing data to ensure reliable and accurate interpretation of findings. Regulatory and academic partnerships should be fostered to provide an independent and transparent evaluation of drug safety.

Effectiveness of a web-based colorectal cancer screening patient decision aid: a randomized controlled trial in a mixed-literacy population.

BACKGROUND: Colorectal cancer (CRC) screening reduces mortality yet remains underutilized. Low health literacy may contribute to this underutilization by interfering with patients' ability to understand and receive preventive health services. PURPOSE: To determine if a web-based multimedia CRC screening patient decision aid, developed for a mixed-literacy audience, could increase CRC screening. DESIGN: RCT. Patients aged 50-74 years and overdue for CRC screening were randomized to the web-based decision aid or a control program seen immediately before a scheduled primary care appointment. SETTING/PARTICIPANTS: A large community-based, university-affiliated internal medicine practice serving a socioeconomically disadvantaged population. MAIN OUTCOME MEASURES: Patients completed surveys to determine their ability to state a screening test preference and their readiness to receive screening. Charts were abstracted by masked observers to determine if screening tests were ordered and completed. RESULTS: Between November 2007 and September 2008, a total of 264 patients enrolled in the study. Data collection was completed in 2009, and data analysis was completed in 2010. A majority of participants (mean age=57.8 years) were female (67%), African-American (74%), had annual household incomes of <$20,000 (76%), and had limited health literacy (56%). When compared to control participants, more decision-aid participants had a CRC screening preference (84% vs 55%, p<0.0001) and an increase in readiness to receive screening (52% vs 20%, p=0.0001). More decision-aid participants had CRC screening tests ordered (30% vs 21%) and completed (19% vs 14%), but no statistically significant differences were seen (AOR=1.6, 95% CI=0.97, 2.8, and AOR=1.7, 95% CI=0.88, 3.2, respectively). Similar results were found across literacy levels. CONCLUSIONS: The web-based decision aid increased patients' ability to form a test preference and their intent to receive screening, regardless of literacy level. Further study should examine ways the decision aid can be combined with additional system changes to increase CRC screening.

Prevalence of mental disorders and torture among Bhutanese refugees in Nepal: a systemic review and its policy implications.

The mass expulsion and exile of Bhutanese de facto refugees to displaced camps in Nepal represents one of the world's most neglected humanitarian crises. We aimed to summarize the impact of the long-term displacement on refugee mental illness using systematic review techniques, a methodology seldom used in the humanitarian field. In order to examine the impact among the population and the association between tortured refugees over non-tortured refugees, we searched 11 electronic databases from inception to 12 May 2006. We additionally contacted researchers at the United Nations High Commission for Refugees (UNHCR) and at the Centre for Victims of Torture, Kathmandu, and searched the websites of Amnesty International, Human Rights Watch, Relief-Web, and the US State Department. We included any studies that use a pre-defined protocol to determine mental illness within this population. Six studies met our inclusion criteria. All were conducted amongst the Bhutanese populations residing in Nepalese refugee camps, and include a sub-sample of 2,331 torture survivors residing in the camps, identified in 1995. All studies report a dramatically high incidence of mental illness including depression, anxiety and post-traumatic stress disorder. Both tortured and non-tortured participants reported elevated rates of mental illness. Our review indicates that the prevalence of serious mental health disorders within this population is elevated. The reported incidence of torture is a possible contributor to the illnesses. The use of systematic review techniques strengthens the inference that systematic human rights violations were levied upon this population and that they continue to suffer as a result. The international community must resolve this protracted crisis.