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.

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.

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.

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.

Display of cell surface sites for fibronectin assembly is modulated by cell adherence to (1)F3 and C-terminal modules of fibronectin.

BACKGROUND: Fibronectin-null cells assemble soluble fibronectin shortly after adherence to a substrate coated with intact fibronectin but not when adherent to the cell-binding domain of fibronectin (modules (7)F3-(10)F3). Interactions of adherent cells with regions of adsorbed fibronectin other than modules (7)F3-(10)F3, therefore, are required for early display of the cell surface sites that initiate and direct fibronectin assembly. METHODOLOGY/PRINCIPAL FINDINGS: To identify these regions, coatings of proteolytically derived or recombinant pieces of fibronectin containing modules in addition to (7)F3-(10)F3 were tested for effects on fibronectin assembly by adherent fibronectin-null fibroblasts. Pieces as large as one comprising modules (2)F3-(14)F3, which include the heparin-binding and cell adhesion domains, were not effective in supporting fibronectin assembly. Addition of module (1)F3 or the C-terminal modules to modules (2)F3-(14)F3 resulted in some activity, and addition of both (1)F3 and the C-terminal modules resulted in a construct, (1)F3-C, that best mimicked the activity of a coating of intact fibronectin. Constructs (1)F3-C V0, (1)F3-C V64, and (1)F3-C Delta(V(15)F3(10)F1) were all able to support fibronectin assembly, suggesting that (1)F3 through (11)F1 and/or (12)F1 were important for activity. Coatings in which the active parts of (1)F3-C were present in different proteins were much less active than intact (1)F3-C. CONCLUSIONS: These results suggest that (1)F3 acts together with C-terminal modules to induce display of fibronectin assembly sites on adherent cells.

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.

PARTAKE survey of public knowledge and perceptions of clinical research in India.

BACKGROUND: A public that is an informed partner in clinical research is important for ethical, methodological, and operational reasons. There are indications that the public is unaware or misinformed, and not sufficiently engaged in clinical research but studies on the topic are lacking. PARTAKE - Public Awareness of Research for Therapeutic Advancements through Knowledge and Empowerment is a program aimed at increasing public awareness and partnership in clinical research. The PARTAKE Survey is a component of the program. OBJECTIVE: To study public knowledge and perceptions of clinical research. METHODS: A 40-item questionnaire combining multiple-choice and open-ended questions was administered to 175 English- or Hindi-speaking individuals in 8 public locations representing various socioeconomic strata in New Delhi, India. RESULTS: Interviewees were 18-84 old (mean: 39.6, SD ± 16.6), 23.6% female, 68.6% employed, 7.3% illiterate, 26.3% had heard of research, 2.9% had participated and 58.9% expressed willingness to participate in clinical research. The following perceptions were reported (% true/% false/% not aware): 'research benefits society' (94.1%/3.5%/2.3%), 'the government protects against unethical clinical research' (56.7%/26.3%/16.9%), 'research hospitals provide better care' (67.2%/8.7%/23.9%), 'confidentiality is adequately protected' (54.1%/12.3%/33.5%), 'participation in research is voluntary' (85.3%/5.8%/8.7%); 'participants treated like 'guinea pigs'' (20.7%/53.2%/26.0%), and 'compensation for participation is adequate' (24.7%/12.9%/62.3%). CONCLUSIONS: Results suggest the Indian public is aware of some key features of clinical research (e.g., purpose, value, voluntary nature of participation), and supports clinical research in general but is unaware of other key features (e.g., compensation, confidentiality, protection of human participants) and exhibits some distrust in the conduct and reporting of clinical trials. Larger, cross-cultural surveys are required to inform educational programs addressing these issues.

Polymorphisms in the kinesin-like factor 1 B gene and risk of epithelial ovarian cancer in Eastern Chinese women.

The kinesin-like factor 1 B (KIF1B) gene plays an important role in the process of apoptosis and the transformation and progression of malignant cells. Genetic variations in KIF1B may contribute to risk of epithelial ovarian cancer (EOC). In this study of 1,324 EOC patients and 1,386 cancer-free female controls, we investigated associations between two potentially functional single nucleotide polymorphisms in KIF1B and EOC risk by the conditional logistic regression analysis. General linear regression model was used to evaluate the correlation between the number of variant alleles and KIF1B mRNA expression levels. We found that the rs17401966 variant AG/GG genotypes were significantly associated with a decreased risk of EOC (adjusted odds ratio (OR) = 0.81, 95 % confidence interval (CI) = 0.68-0.97), compared with the AA genotype, but no associations were observed for rs1002076. Women who carried both rs17401966 AG/GG and rs1002076 AG/AA genotypes of KIF1B had a 0.82-fold decreased risk (adjusted 95 % CI = 0.69-0.97), compared with others. Additionally, there was no evidence of possible interactions between about-mentioned co-variants. Further genotype-phenotype correlation analysis indicated that the number of rs17401966 variant G allele was significantly associated with KIF1B mRNA expression levels (P for GLM = 0.003 and 0.001 in all and Chinese subjects, respectively), with GG carriers having the lowest level of KIF1B mRNA expression. Taken together, the rs17401966 polymorphism likely regulates KIF1B mRNA expression and thus may be associated with EOC risk in Eastern Chinese women. Larger, independent studies are warranted to validate our findings.

Weight loss intervention for young adults using mobile technology: design and rationale of a randomized controlled trial - Cell Phone Intervention for You (CITY).

BACKGROUND: The obesity epidemic has spread to young adults, leading to significant public health implications later in adulthood. Intervention in early adulthood may be an effective public health strategy for reducing the long-term health impact of the epidemic. Few weight loss trials have been conducted in young adults. It is unclear what weight loss strategies are beneficial in this population. PURPOSE: To describe the design and rationale of the NHLBI-sponsored Cell Phone Intervention for You (CITY) study, which is a single center, randomized three-arm trial that compares the impact on weight loss of 1) a behavioral intervention that is delivered almost entirely via cell phone technology (Cell Phone group); and 2) a behavioral intervention delivered mainly through monthly personal coaching calls enhanced by self-monitoring via cell phone (Personal Coaching group), each compared to 3) a usual care, advice-only control condition. METHODS: A total of 365 community-dwelling overweight/obese adults aged 18-35 years were randomized to receive one of these three interventions for 24 months in parallel group design. Study personnel assessing outcomes were blinded to group assignment. The primary outcome is weight change at 24 [corrected] months. We hypothesize that each active intervention will cause more weight loss than the usual care condition. Study completion is anticipated in 2014. CONCLUSIONS: If effective, implementation of the CITY interventions could mitigate the alarming rates of obesity in young adults through promotion of weight loss. ClinicalTrial.gov: NCT01092364.

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.