Knowledge and Perceptions about Clinical Trials and the Use of Biomedical Samples: Findings from a Qualitative Study in Rural Northern Ghana

IntroductionClinical trials conducted in sub-Saharan Africa have helped to address the prevalent health challenges. The knowledge about how communities perceive clinical trials is however only now evolving. This study was conducted among parents whose children participated in past clinical trials in northern Ghana to assess their knowledge and perceptions of clinical trials and the use of biomedical samples.MethodThis was a qualitative study based on eighty in-depth interviews with parents. The participants were randomly selected from among parents whose children were enrolled in a clinical trial conducted in the Kassena-Nankana districts between 2000 and 2003. The interviews were transcribed and coded into emergent themes using Nvivo 9 software. The thematic analysis framework was used to analyze the data.ResultsStudy participants reported that clinical trials were carried out to determine the efficacy of drugs and to make sure that these drugs were suitable for human beings to use. The conduct of clinical trials was perceived to have helped to reduce the occurrence of diseases such as malaria, cerebrospinal meningitis and diarrhea. Quality of care was reported to be better in clinical trials than in the routine care. Parents indicated that participation in clinical trials positively influenced their health-seeking behavior. Apprehensions about blood draw and the use to which samples were put were expressed, with suspicion by a few participants that researchers sold blood samples. The issue of blood draw was most contentious.ConclusionParents perception about the conduct of clinical trials in the study districts is generally positive. However, misconceptions made about the use of blood samples in this study must be taken seriously and strategies found to improve transparency and greater community acceptability.     

Parents’ Agendas in Paediatric Clinical Trial Recruitment Are Different from Researchers’ and Often Remain Unvoiced: A Qualitative Study

Ensuring parents make an informed decision about their child’s participation in a clinical trial is a challenge for practitioners as a parent’s comprehension of a trial may differ from that intended by the practitioners responsible for recruitment. We explored what issues parents consider important when making a decision about participation in a paediatric clinical trial and their comprehension of these issues to inform future recruitment practice. This qualitative interview and observational study examined recruitment in four placebo-controlled, double-blind randomised clinical trials of medicines for children. Audio-recorded trial recruitment discussions between practitioners and parents (N = 41) were matched with semi-structured interviews with parents (N = 41). When making a decision about trial entry parents considered clinical benefit, child safety, practicalities of participation, research for the common good, access to medication and randomisation. Within these prioritised issues parents had specific misunderstandings, which had the potential to influence their decisions. While parents had many questions and concerns about trial participation which influenced their decision-making, they rarely voiced these during discussions about the trials with practitioners. Those involved in the recruitment of children to clinical trials need to be aware of parents’ priorities and the sorts of misunderstandings that can arise with parents. Providing trial information that is tailored to what parents consider important in making a decision about a clinical trial may improve recruitment practice and ultimately benefit evidence-based paediatric medicine.     

Parents of Adolescents with Type 1 Diabetes - Their Views on Information and Communication Needs and Internet Use. A Qualitative Study

Background

Little is known about parents’ views on the use of online resources for information, education and support regarding childhood type 1 diabetes (T1DM). Considering the rapidly evolving new communication practices, parents’ perspectives need to be explored. The main purpose of this paper was to explore parents’ perceptions of their information-seeking, Internet use, and social networking online. This applied to their everyday life, including the contexts of T1DM and contact with peers. A second aim was to identify implications for future development of Internet use in this respect.

Methodology/Principal Findings

Twenty-seven parents of 24 young persons aged 10–17 with T1DM participated in eight focus group interviews during their regular visits to a county hospital. Focus group discussions were video/audio-taped, transcribed and analysed using inductive qualitative content analysis. Self-reported demographic and medical information was also collected. A main theme was Finding things out, including two sub-themes, Trust and Suitability. The latter were key factors affecting parents’ perceptions of online resources. Parents’ choice of information source was related to the situation, previous experiences and knowledge about sources and, most importantly, the level of trust in the source. A constantly present background theme was Life situation, including two sub-themes, Roles and functions and Emotions and needs. Parents’ information-seeking regarding T1DM varied greatly, and was closely associated with their life situation, the adolescents development phases and the disease trajectory.

Conclusions/Significance

Health practitioners and system developers need to focus on creating trust and suitability for users’ needs. They should understand the children’s diverse needs, which depend on their life situation, on the children’s development, and on the disease trajectory. To enhance trust in online health information and support services, the participation of local practitioners is crucial.     

Use of Concomitant Glucose-Lowering Therapies and Associated Treatment Results Observed in Clinical Trials of Twice-Daily Exenatide

ObjectiveTo explore, by post hoc analyses of pooled data, the efficacy and safety of the use of exenatide twice daily (BID) in patients stratified by baseline glucose-low ering therapies.MethodsPatients with type 2 diabetes from long term randomized controlled trials who were treated with exenatide BID were classified into concomitant medica tion groups on the basis of background treatment (diet and exercise only, metformin only, sulfonylurea only, thia zolidinedione only, metformin + sulfonylurea, metformin + thiazolidinedione, or insulin with or without other oral antihyperglycemic medications). Seventeen studies were included in the analyses (N = 2,096).ResultsIn these analyses of patients treated with exenatide BID for 12 to 30 weeks, there were significant decreases from baseline in hemoglobin A_1c (A1C) and fast ing glucose levels in all groups and significant decreases from baseline in body weight in all groups except the thi azolidinedione-only group. The decrease in A1C appeared to be greater in the insulin group than in the other groups, likely because the insulin dose was titrated whereas doses of concomitant antihyperglycemic medications were gen erally not titrated. Overall, changes in blood pressure and lipids were small. Across all groups, the most common adverse effects were gastrointestinal events. Hypoglycemia was more common in the sulfonylurea-only, metformin + sulfonylurea, and insulin groups than it was in the other concomitant medication groups.ConclusionThe use of exenatide BID across a wide range of background therapies was associated with reductions in A1C, fasting glucose, and body weight. Gastrointestinal adverse events were common. (Endocr Pract. 2012;18:227-237)     

临床试验进展：大数据方法在临床试验中的应用

药物研发的复杂性与日俱增,而大数据时代的到来使得临床试验的进展大大加快。本期“临床试验进展”讨论了皮肤病学新创试验中面向数据的亮点,探讨了现实采用的大数据方法,剖析了对风险导向监察的新兴方法学。此外还汇总了银屑病和特应性皮炎新疗法的临床研究报告,揭示了这些疾病的影响以及Ⅱ期和Ⅲ期研究中已经取得成功的候选药。     

General Practitioners Views of Implementing a Stratified Treatment Approach for Low Back Pain in Germany: A Qualitative Study

Background and Objective

The STarT Back stratified primary care approach has demonstrated clinical and cost effectiveness in the UK, and is commonly used by General Practitioners (GPs). However, it remains unknown how this approach could be implemented into the German healthcare system. The aim of this study was therefore to explore the views and perceptions of German GPs in respect to using a stratified primary care for low back pain (LBP).

Methods

A 90-minute think-tank workshop was conducted with 14 male and five female GPs, during which the STarT-Back-Screening-Tool (SBST) and related research evidence was presented. This was followed by two focus groups, based on a semi-structured interview guideline to identify potential implementation barriers and opportunities. Discussions were audiotaped, transcribed and coded using a content analysis approach.

Results

For the three deductively developed main themes, 15 subthemes emerged: (1) application of the SBST, with the following subthemes: which health profession should administer it, patients known to the GP practice, the reason for the GP consultation, scoring the tool, the tool format, and the anticipated impact on GP practice; (2) psychologically informed physiotherapy, with subthemes including: provision by a physiotherapist, anticipated impact, the skills of physiotherapists, management of patients with severe psychosocial problems, referral and remuneration; (3) the management of low-risk patients, with subthemes including: concern about the appropriate advising health professional, information and media, length of consultation, and local exercise venues.

Conclusions

The attitudes of GPs towards stratified primary care for LBP indicated positive support for pilot-testing in Germany. However, there were mixed reactions to the ability of German physiotherapists to manage high-risk patients and handle their complex clinical needs. GPs also mentioned practical difficulties in providing extended advice to low-risk patients, which nevertheless could be addressed by involvement of specifically trained medical assistants.     

Virologic Response to Tipranavir-Ritonavir or Darunavir-Ritonavir Based Regimens in Antiretroviral Therapy Experienced HIV-1 Patients: A Meta-Analysis and Meta-Regression of Randomized Controlled Clinical Trials

Background

The development of tipranavir and darunavir, second generation non-peptidic HIV protease inhibitors, with marked improved resistance profiles, has opened a new perspective on the treatment of antiretroviral therapy (ART) experienced HIV patients with poor viral load control. The aim of this study was to determine the virologic response in ART experienced patients to tipranavir-ritonavir and darunavir-ritonavir based regimens.

Methods and Findings

A computer based literature search was conducted in the databases of HINARI (Health InterNetwork Access to Research Initiative), Medline and Cochrane library. Meta-analysis was performed by including randomized controlled studies that were conducted in ART experienced patients with plasma viral load above 1,000 copies HIV RNA/ml. The odds ratios and 95% confidence intervals (CI) for viral loads of <50 copies and <400 copies HIV RNA/ml at the end of the intervention were determined by the random effects model. Meta-regression, sensitivity analysis and funnel plots were done. The number of HIV-1 patients who were on either a tipranavir-ritonavir or darunavir-ritonavir based regimen and achieved viral load less than 50 copies HIV RNA/ml was significantly higher (overall OR = 3.4; 95% CI, 2.61– 4.52) than the number of HIV-1 patients who were on investigator selected boosted comparator HIV-1 protease inhibitors (CPIs-ritonavir). Similarly, the number of patients with viral load less than 400 copies HIV RNA/ml was significantly higher in either the tipranavir-ritonavir or darunavir-ritonavir based regimen treated group (overall OR = 3.0; 95% CI, 2.15 – 4.11). Meta-regression showed that the viral load reduction was independent of baseline viral load, baseline CD4 count and duration of tipranavir-ritonavir or darunavir-ritonavir based regimen.

Conclusions

Tipranavir and darunavir based regimens were more effective in patients who were ART experienced and had poor viral load control. Further studies are required to determine their consistent viral load suppression effect as the duration of treatment is more prolonged.     

临床试验进展：临床数据与实验室质量管理规范

将临床研究数据用于临床日常规范及健康相关决策的制定对于改善全球医疗保健至关重要。汤森路透Cortellis 临床试验情报对临床试验数据的应用价值及各国临床实验室质量管理规范的实施情况进行了介绍,提供描绘临床图景关键元素和当前趋势的专家分析,从而指导临床开发决策。     

Centre Selection for Clinical Trials and the Generalisability of Results: A Mixed Methods Study

Background

The rationale for centre selection in randomised controlled trials (RCTs) is often unclear but may have important implications for the generalisability of trial results. The aims of this study were to evaluate the factors which currently influence centre selection in RCTs and consider how generalisability considerations inform current and optimal practice.

Methods and Findings

Mixed methods approach consisting of a systematic review and meta-summary of centre selection criteria reported in RCT protocols funded by the UK National Institute of Health Research (NIHR) initiated between January 2005-January 2012; and an online survey on the topic of current and optimal centre selection, distributed to professionals in the 48 UK Clinical Trials Units and 10 NIHR Research Design Services. The survey design was informed by the systematic review and by two focus groups conducted with trialists at the Birmingham Centre for Clinical Trials. 129 trial protocols were included in the systematic review, with a total target sample size in excess of 317,000 participants. The meta-summary identified 53 unique centre selection criteria. 78 protocols (60%) provided at least one criterion for centre selection, but only 31 (24%) protocols explicitly acknowledged generalisability. This is consistent with the survey findings (n = 70), where less than a third of participants reported generalisability as a key driver of centre selection in current practice. This contrasts with trialists’ views on optimal practice, where generalisability in terms of clinical practice, population characteristics and economic results were prime considerations for 60% (n = 42), 57% (n = 40) and 46% (n = 32) of respondents, respectively.

Conclusions

Centres are rarely enrolled in RCTs with an explicit view to external validity, although trialists acknowledge that incorporating generalisability in centre selection should ideally be more prominent. There is a need to operationalize ‘generalisability’ and incorporate it at the design stage of RCTs so that results are readily transferable to ‘real world’ practice.     

Placebo Devices as Effective Control Methods in Acupuncture Clinical Trials: A Systematic Review

While the use of acupuncture has been recognised by the World Health Organisation, its efficacy for many of the common clinical conditions is still undergoing validation through randomised controlled trials (RCTs). A credible placebo control for such RCTs to enable meaningful evaluation of its efficacy is to be established. While several non-penetrating acupuncture placebo devices, namely the Streitberger, the Park and the Takakura Devices, have been developed and used in RCTs, their suitability as inert placebo controls needs to be rigorously determined. This article systematically reviews these devices as placebo interventions. Electronic searches were conducted on four English and two Chinese databases from their inceptions to July 2014; hand searches of relevant references were also conducted. RCTs, in English or Chinese language, comparing acupuncture with one of the aforementioned devices as the control intervention on human participants with any clinical condition and evaluating clinically related outcomes were included. Thirty-six studies were included for qualitative analysis while 14 were in the meta-analysis. The meta-analysis does not support the notion of either the Streitberger or the Park Device being inert control interventions while none of the studies involving the Takakura Device was included in the meta-analysis. Sixteen studies reported the occurrence of adverse events, with no significant difference between verum and placebo acupuncture. Author-reported blinding credibility showed that participant blinding was successful in most cases; however, when blinding index was calculated, only one study, which utilised the Park Device, seemed to have an ideal blinding scenario. Although the blinding index could not be calculated for the Takakura Device, it was the only device reported to enable practitioner blinding. There are limitations with each of the placebo devices and more rigorous studies are needed to further evaluate their effects and blinding credibility.     

Fat Talk: What Girls and Their Parents Say about Dieting

Fat Talk: What Girls and Their Parents Say about Dieting. Mimi Nichter. Cambridge, MA: Harvard University Press, 2000. xi. 262 pp.     

临床试验进展: 适应性设计及透明性

临床试验中的适应性设计是根据累积信息来修正试验的一种设计方法,旨在使临床试验和临床开发计划效率更高,并为患者提供更加有效的治疗。此外,因信息隐匿造成试验失败和患者死亡,从而导致公众对医药行业的信任度下降,故关于公开临床数据的观点已开始朝着提升透明度方向调整。介绍3 类适应性设计方法的特点和应用,以及国外药政部门和制药企业对提高临床试验透明性的举措。     

Observed and Predicted Risk of Breast Cancer Death in Randomized Trials on Breast Cancer Screening

BackgroundThe role of breast screening in breast cancer mortality declines is debated. Screening impacts cancer mortality through decreasing the number of advanced cancers with poor diagnosis, while cancer treatment works through decreasing the case-fatality rate. Hence, reductions in cancer death rates thanks to screening should directly reflect reductions in advanced cancer rates. We verified whether in breast screening trials, the observed reductions in the risk of breast cancer death could be predicted from reductions of advanced breast cancer rates.ResultsThe observed and predicted RR of breast cancer death were 0.72 (0.56–0.94) and 0.98 (0.77–1.24) in the HIP trial, and 0.79 (0.78–1.01) and 0.90 (0.80–1.01) in the Age trial. In the TCT, the observed RR was 0.73 (0.62–0.87), while the predicted RR was 0.89 (0.75–1.05) if overdiagnosis was assumed to be negligible and 0.83 (0.70–0.97) if extra cancers were excluded.ConclusionsIn breast screening trials, factors other than screening have contributed to reductions in the risk of breast cancer death most probably by reducing the fatality of advanced cancers in screening groups. These factors were the better management of breast cancer patients and the underreporting of breast cancer as the underlying cause of death. Breast screening trials should publish stage-specific fatalities observed in each group.     

Evidence for the Selective Reporting of Analyses and Discrepancies in Clinical Trials: A Systematic Review of Cohort Studies of Clinical Trials

Background

Most publications about selective reporting in clinical trials have focussed on outcomes. However, selective reporting of analyses for a given outcome may also affect the validity of findings. If analyses are selected on the basis of the results, reporting bias may occur. The aims of this study were to review and summarise the evidence from empirical cohort studies that assessed discrepant or selective reporting of analyses in randomised controlled trials (RCTs).

Methods and Findings

A systematic review was conducted and included cohort studies that assessed any aspect of the reporting of analyses of RCTs by comparing different trial documents, e.g., protocol compared to trial report, or different sections within a trial publication. The Cochrane Methodology Register, Medline (Ovid), PsycInfo (Ovid), and PubMed were searched on 5 February 2014. Two authors independently selected studies, performed data extraction, and assessed the methodological quality of the eligible studies. Twenty-two studies (containing 3,140 RCTs) published between 2000 and 2013 were included. Twenty-two studies reported on discrepancies between information given in different sources. Discrepancies were found in statistical analyses (eight studies), composite outcomes (one study), the handling of missing data (three studies), unadjusted versus adjusted analyses (three studies), handling of continuous data (three studies), and subgroup analyses (12 studies). Discrepancy rates varied, ranging from 7% (3/42) to 88% (7/8) in statistical analyses, 46% (36/79) to 82% (23/28) in adjusted versus unadjusted analyses, and 61% (11/18) to 100% (25/25) in subgroup analyses. This review is limited in that none of the included studies investigated the evidence for bias resulting from selective reporting of analyses. It was not possible to combine studies to provide overall summary estimates, and so the results of studies are discussed narratively.

Conclusions

Discrepancies in analyses between publications and other study documentation were common, but reasons for these discrepancies were not discussed in the trial reports. To ensure transparency, protocols and statistical analysis plans need to be published, and investigators should adhere to these or explain discrepancies. Please see later in the article for the Editors'' Summary     

上海市医疗机构基因临床研究与应用的现状分析

?????? 目的 分析上海市基因临床研究与应用中存在或可能存在的伦理问题。方法 对上海市22所医疗机构进行问卷调查,并对相关人员进行关键知情者访谈。结果 被调查的上海市医疗机构中有7所开展基因工作,2011年公立医院基因检测平均服务量比2009年增长1.75倍;31%的公立医院从事基因工作的人员在近一年内参加过伦理培训,体检机构未向员工提供伦理培训;3所开展基因检测的机构未要求签署知情同意书。结论 上海市基因临床研究与应用发展较快但应用不广,应进一步促进基因检测技术的临床应用,完善基因临床应用的伦理规范。     

Remote Source Document Verification in Two National Clinical Trials Networks: A Pilot Study

Objective

Barriers to executing large-scale randomized controlled trials include costs, complexity, and regulatory requirements. We hypothesized that source document verification (SDV) via remote electronic monitoring is feasible.

Methods

Five hospitals from two NIH sponsored networks provided remote electronic access to study monitors. We evaluated pre-visit remote SDV compared to traditional on-site SDV using a randomized convenience sample of all study subjects due for a monitoring visit. The number of data values verified and the time to perform remote and on-site SDV was collected.

Results

Thirty-two study subjects were randomized to either remote SDV (N=16) or traditional on-site SDV (N=16). Technical capabilities, remote access policies and regulatory requirements varied widely across sites. In the adult network, only 14 of 2965 data values (0.47%) could not be located remotely. In the traditional on-site SDV arm, 3 of 2608 data values (0.12%) required coordinator help. In the pediatric network, all 198 data values in the remote SDV arm and all 183 data values in the on-site SDV arm were located. Although not statistically significant there was a consistent trend for more time consumed per data value (minutes +/- SD): Adult 0.50 +/- 0.17 min vs. 0.39 +/- 0.10 min (two-tailed t-test p=0.11); Pediatric 0.99 +/- 1.07 min vs. 0.56 +/- 0.61 min (p=0.37) and time per case report form: Adult: 4.60 +/- 1.42 min vs. 3.60 +/- 0.96 min (p=0.10); Pediatric: 11.64 +/- 7.54 min vs. 6.07 +/- 3.18 min (p=0.10) using remote SDV.

Conclusions

Because each site had different policies, requirements, and technologies, a common approach to assimilating monitors into the access management system could not be implemented. Despite substantial technology differences, more than 99% of data values were successfully monitored remotely. This pilot study demonstrates the feasibility of remote monitoring and the need to develop consistent access policies for remote study monitoring.     

Estimating Allee Dynamics before They Can Be Observed: Polar Bears as a Case Study

Allee effects are an important component in the population dynamics of numerous species. Accounting for these Allee effects in population viability analyses generally requires estimates of low-density population growth rates, but such data are unavailable for most species and particularly difficult to obtain for large mammals. Here, we present a mechanistic modeling framework that allows estimating the expected low-density growth rates under a mate-finding Allee effect before the Allee effect occurs or can be observed. The approach relies on representing the mechanisms causing the Allee effect in a process-based model, which can be parameterized and validated from data on the mechanisms rather than data on population growth. We illustrate the approach using polar bears (Ursus maritimus), and estimate their expected low-density growth by linking a mating dynamics model to a matrix projection model. The Allee threshold, defined as the population density below which growth becomes negative, is shown to depend on age-structure, sex ratio, and the life history parameters determining reproduction and survival. The Allee threshold is thus both density- and frequency-dependent. Sensitivity analyses of the Allee threshold show that different combinations of the parameters determining reproduction and survival can lead to differing Allee thresholds, even if these differing combinations imply the same stable-stage population growth rate. The approach further shows how mate-limitation can induce long transient dynamics, even in populations that eventually grow to carrying capacity. Applying the models to the overharvested low-density polar bear population of Viscount Melville Sound, Canada, shows that a mate-finding Allee effect is a plausible mechanism for slow recovery of this population. Our approach is generalizable to any mating system and life cycle, and could aid proactive management and conservation strategies, for example, by providing a priori estimates of minimum conservation targets for rare species or minimum eradication targets for pests and invasive species.