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.     

A Bayesian model with application for adaptive platform trials having temporal changes

Temporal changes exist in clinical trials. Over time, shifts in patients' characteristics, trial conduct, and other features of a clinical trial may occur. In typical randomized clinical trials, temporal effects, that is, the impact of temporal changes on clinical outcomes and study analysis, are largely mitigated by randomization and usually need not be explicitly addressed. However, temporal effects can be a serious obstacle for conducting clinical trials with complex designs, including the adaptive platform trials that are gaining popularity in recent medical product development. In this paper, we introduce a Bayesian robust prior for mitigating temporal effects based on a hidden Markov model, and propose a particle filtering algorithm for computation. We conduct simulation studies to evaluate the performance of the proposed method and provide illustration examples based on trials of Ebola virus disease therapeutics and hemostat in vascular surgery.     

Photodynamic therapy for cutaneous leishmaniasis: the effectiveness of topical phenothiaziniums in parasite eradication and Th1 immune response stimulation.

Photodynamic therapy (PDT) is emerging as a therapeutic modality in the clinical management of cutaneous leishmaniasis (CL). The efficacy of PDT against CL has been demonstrated previously with aminolevulinic acid, although the prolonged terms of therapy were less than ideal, and the search for new photosensitizers (PS) is ongoing. However, phenothiaziniums have demonstrated high parasiticidal effects in vitro. The subject of our investigation is the in vivo activity of two PS, 5-ethylamino-9-diethylaminobenzo[a]phenoselenazinium chloride (EtNBSe) and (3,7-Bis(N,N-dibutylamino) phenothiazinium bromide (PPA904). The results of our comparative analysis of the efficacy of these two phenothiazinium analogues demonstrated a high antiparasitic activity of EtNBSe in vitro, and the higher efficacy of PPA904 in a mouse model of CL. The kinetics of photodestruction are different in parasite and mammalian cells, and with both dyes, the macrophages are more susceptible to photodynamic effects than L. major parasites. As the number of parasites in the lesions undergoes a biphasic change, temporarily increasing on days 2-4 and decreasing on days 5-7, more than one treatment is required within an interval of 5 to 7 days. We have also shown that PPA904-PDT can provide an immunomodulating, dose-dependent efflux on IL-12p70 production. This mechanism could be responsible for promoting a more rapid healing in PPA904-PDT treated mice. Our initial data indicate that phenothiaziniums exhibit a high parasiticidal effect in vivo against CL; this finding may be of use in establishing curative PDT regimens for future clinical trials.     

Information giving in clinical trials: the views of medical researchers

It is both an ethical and a legal requirement that patients who participate in clinical trials must generally give their consent. As part of this process, patients must be provided with adequate information to enable them to decide whether or not to take part. In the UK, the pharmaceutical companies that sponsor such research, as well as Local Research Ethics Committees, specify in detail the information that must be given to trial participants. The researchers who conduct clinical trials inevitably form views on the amount of information they are required to provide, and about patients' comprehension of that information. The literature in this area suggests that some medical researchers may be unhappy with the amount of information that they must give patient participants. There have been, however, few systematic attempts to determine their views. This paper reports a study that explored researchers' views as to (i) the amount of information provided to trial participants, and (ii) participants' understanding of that information. Researchers generally felt that they were required to give trial participants an appropriate amount of information, and that most patients had at least a reasonable understanding of key aspects of the clinical trials' process. However, there were differing views as to the level of information that they felt patients themselves wanted. The researchers did not generally feel that the patients' inability to comprehend information rendered the process of obtaining 'informed consent' a waste of time. However, some did believe that they were required to burden patients with excessive information.     

Generalized Estimating Equations in Controlled Clinical Trials: Hypotheses Testing

Generalized estimating equations (GEE) for the analysis of clustered data have gained increasing popularity. Recently, the first monograph on this method has been published. GEE have been repeatedly applied in controlled clinical trials. They have, however, been generally used as secondary or supplementary analysis. Instead, the primary analysis was mostly based on a classical method that usually ignored the clustered – mostly longitudinal – nature of the data. In this paper, we discuss the applicability of GEE as primary analysis in controlled clinical trials. From theoretical results in the literature, we derive recommendations how GEE should be used in therapeutic studies for testing statistical hypotheses. We hope that our paper is the starting point for a thorough discussion on the most appropriate analysis of controlled clinical trials with clustered dependent variables. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Understanding the biology of sex and gender differences: using subgroup analysis and statistical design to detect sex differences in clinical trials

In May 2000, a General Accounting Office (GAO) report revealed that although women are now participating in clinical trials in numbers proportionate to their numbers in the general population, data collected in these trials are not routinely analyzed by sex.[1] Without such sex analysis, clinically relevant information about potentially lifesaving treatments could be lost. In July 2001, the Society for Women's Health Research convened a workshop to address strategies for conducting subgroup analyses to detect sex differences. Workshop participants concluded that understanding sex differences will enable medical researchers to design healthcare interventions for both men and women more effectively and that one can plan for and conduct sex analysis without compromising the quality of the study or making the study prohibitively expensive.     

Is Paromomycin an Effective and Safe Treatment against Cutaneous Leishmaniasis? A Meta-Analysis of 14 Randomized Controlled Trials

Background

High cost, poor compliance, and systemic toxicity have limited the use of pentavalent antimony compounds (SbV), the treatment of choice for cutaneous leishmaniasis (CL). Paromomycin (PR) has been developed as an alternative to SbV, but existing data are conflicting.

Methodology/Principal Findings

We searched PubMed, Scopus, and Cochrane Central Register of Controlled Trials, without language restriction, through August 2007, to identify randomized controlled trials that compared the efficacy or safety between PR and placebo or SbV. Primary outcome was clinical cure, defined as complete healing, disappearance, or reepithelialization of all lesions. Data were extracted independently by two investigators, and pooled using a random-effects model. Fourteen trials including 1,221 patients were included. In placebo-controlled trials, topical PR appeared to have therapeutic activity against the old world and new world CL, with increased local reactions, when used with methylbenzethonium chloride (MBCL) compared to when used alone (risk ratio [RR] for clinical cure, 2.58 versus 1.01: RR for local reactions, 1.60 versus 1.07). In SbV-controlled trials, the efficacy of topical PR was not significantly different from that of intralesional SbV in the old world CL (RR, 0.70; 95% confidence interval, 0.26–1.89), whereas topical PR was inferior to parenteral SbV in treating the new world CL (0.67; 0.54–0.82). No significant difference in efficacy was found between parenteral PR and parenteral SbV in the new world CL (0.88; 0.56–1.38). Systemic side effects were fewer with topical or parenteral PR than parenteral SbV.

Conclusions/Significance

Topical PR with MBCL could be a therapeutic alternative to SbV in selected cases of the old world CL. Development of new formulations with better efficacy and tolerability remains to be an area of future research.     

Ginseng for Health Care: A Systematic Review of Randomized Controlled Trials in Korean Literature

Objective

This systematic review was performed to summarise randomised clinical trials (RCTs) assessing the efficacy and safety of ginseng in the Korean literature.

Method

The study involved systematic searches conducted in eight Korean Medical databases. The methodological quality of all of the included studies was assessed using the Cochrane Risk of Bias tool. We included all RCTs on any type of ginseng compared to placebo, active treatment or no treatment in healthy individuals or patients regardless of conditions.

Results

In total, 1415 potentially relevant studies were identified, and 30 randomised clinical trials were included. Nine RCTs assessed the effects of ginseng on exercise capacity, cognitive performance, somatic symptoms, quality of life, and sleeping in healthy persons. Six RCTs tested ginseng compared with placebo for erectile dysfunction, while another four studies evaluated the effects of ginseng against no treatment for gastric and colon cancer. Two RCTs compared the effect of red ginseng on diabetes mellitus with no treatment or placebo, and the other nine RCTs assessed the effects of ginseng compared with placebo or no treatment on various conditions. The methodological caveats of the included trials make their contribution to the current clinical evidence of ginseng somewhat limited. However, the 20 newly added trials (66.7% of the 30 trials) may provide useful information for future trials. Ginseng appears to be generally safe, and no serious adverse effects have been reported.

Conclusions

The clinical effects of ginseng have been tested in a wide range of conditions in Korea. Although the quality of RCTs published in the Korean literature was generally poor, this review is useful for researchers to access studies that were originally published in languages that they would otherwise be unable to read and due to the paucity of evidence on this subject.     

Interim analyses in randomized clinical trials: ramifications and guidelines for practitioners

Recent developments in group sequential methods have had a great impact on the design and analysis of randomized clinical trials. The consequences for both planned and unplanned interim analyses are discussed using several real trials as illustrations. Guidelines for the conduct of interim analysis are given, including tables of nominal significance levels and required sample sizes for several group sequential plans. Areas in need of further theoretical advance include multiple endpoints, estimation of treatment differences, stratification, and design of multiple-armed trials.     

The third Symptom Management Research Trial in Oncology (SMaRT Oncology-3): a randomised trial to determine the efficacy of adding a complex intervention for major depressive disorder (Depression Care for People with Lung Cancer) to usual care, compared to usual care alone in patients with lung cancer

The conduct of clinical trials in the UK has been affected by the recent introduction of managed clinical networks, clinical research networks and rigorous governance regulations. This commentary considers the challenges that these changes have posed for clinical triallists in the UK, based on experiences derived in the conduct of a multicentre neonatal clinical trial under the conditions that now prevail. We conclude that the considerable skills and knowledge that are now required to be an effective Principal Investigator should be recognised and that application processes, including issuing honorary contracts, should be simplified and centralised.     

Meta-analysis of clinical trials with competing time-to-event endpoints

Recommendations for the analysis of competing risks in the context of randomized clinical trials are well established. Meta-analysis of individual patient data (IPD) is the gold standard for synthesizing evidence for clinical interpretation based on multiple studies. Surprisingly, no formal guidelines have been yet proposed to conduct an IPD meta-analysis with competing risk endpoints. To fill this gap, this work details (i) how to handle the heterogeneity between trials via a stratified regression model for competing risks and (ii) that the usual metrics of inconsistency to assess heterogeneity can readily be employed. Our proposal is illustrated by the re-analysis of a recently published meta-analysis in nasopharyngeal carcinoma, aiming at quantifying the benefit of the addition of chemotherapy to radiotherapy on each competing endpoint.     

Do we want more cancer patients on clinical trials If so, what are the barriers to greater accrual

It is often stated that only a small proportion of adult cancer patients participate in clinical trials. This is said to be a bad thing, with calls for more trials to include more patients. Here I argue that whether or not greater accrual to clinical trials would be a good thing depends on the trials we conduct. The vast majority of clinical trials in cancer are currently early phase trials, and most do not lead to further studies even if they have encouraging results. The key metric is thus not the number of patients on clinical trials, but the number on the sort of large, randomized, Phase III trials that can be used as a basis for clinical decisions. I also address two important barriers to greater clinical trial participation. The first barrier is financial: clinical research has long been the poor cousin of basic research, with perhaps no more than a nickel in the cancer research dollar going to clinical research. The second barrier is regulatory: clinical research has become so overburdened by regulation that it takes years to initiate a trial, and dedicated staff just to deal with the paperwork once the trial starts. This not only adds significantly to the costs of clinical research, but scares many young investigators away. It has been estimated that nearly half of all US-sponsored trials are being conducted abroad, and it is plausible that excessive regulation is at least partly responsible. That statistic should serve as a wake-up call to the US clinical research community to implement the recommendations of the now decade-old report of National Cancer Institute Clinical Trials Program Review Group, which largely center around simplifying trials and streamlining trial procedures.     

The potential influence of Internet-based social networking on the conduct of clinical research studies

The rapid growth of internet usage has led to an explosion of social networking sites for discussion of health issues. This provides a forum for subjects to communicate with one another during the course of the studies. Previous studies have raised concerns about the quality of health information on social networking sites, although none have evaluated content related to ongoing clinical trials. We reviewed material posted in virtual communities by self-identified clinical trial participants. We identified material posted in online health forums that could introduce bias into clinical research studies; we believe that this issue warrants further study and discussion. Physicians and others who conduct clinical trials should be aware of this issue. Study investigators and research teams should also talk to their study subjects about where and how they are obtaining information in order to prevent behaviors and correct misinformation that could put a subject's safety or the study objectives at risk. Given the rapid increase in Internet use for health care, a broader evaluation of both the benefits and potential risks of social networking among research participants during the course of a clinical trial appears warranted.     

Comparison of design strategies for a three‐arm clinical trial with time‐to‐event endpoint: Power,time‐to‐analysis,and operational aspects

To optimize resources, randomized clinical trials with multiple arms can be an attractive option to simultaneously test various treatment regimens in pharmaceutical drug development. The motivation for this work was the successful conduct and positive final outcome of a three‐arm randomized clinical trial primarily assessing whether obinutuzumab plus chlorambucil in patients with chronic lympocytic lymphoma and coexisting conditions is superior to chlorambucil alone based on a time‐to‐event endpoint. The inference strategy of this trial was based on a closed testing procedure. We compare this strategy to three potential alternatives to run a three‐arm clinical trial with a time‐to‐event endpoint. The primary goal is to quantify the differences between these strategies in terms of the time it takes until the first analysis and thus potential approval of a new drug, number of required events, and power. Operational aspects of implementing the various strategies are discussed. In conclusion, using a closed testing procedure results in the shortest time to the first analysis with a minimal loss in power. Therefore, closed testing procedures should be part of the statistician's standard clinical trials toolbox when planning multiarm clinical trials.     

Advances in clinical research methodology for pain clinical trials

Pain is a ubiquitous phenomenon, but the experience of pain varies considerably from person to person. Advances in understanding of the growing number of pathophysiologic mechanisms that underlie the generation of pain and the influence of the brain on the experience of pain led to the investigation of numerous compounds for treating pain. Improved knowledge of the subjective nature of pain, the variations in the measurement of pain, the mind-body placebo effect and the impact of differences in the conduct of a clinical trial on the outcome have changed approaches to design and implement studies. Careful consideration of how these concepts affect the choice of study population, the randomization and blinding process, the measurement and collection of data, and the analysis and interpretation of results should improve the quality of clinical trials for potential pain therapies.     

A clinician's guide for conducting randomized trials in individual patients.

In determining optimal treatment for a patient conventional trials of therapy are susceptible to bias. Large-scale randomized trials can provide only a partial guide and have not been or cannot be carried out for most clinical disorders. However, randomized controlled trials (RCTs) in individual patients (N of 1 RCTs) may in some circumstances provide a solution to this dilemma. In an N of 1 RCT a patient undergoes pairs of treatment periods (one period of each pair with the active drug and one with matched placebo, assigned at random); both the patient and the clinician are blind to allocation, and treatment targets are monitored. N of 1 RCTs are useful for chronic, stable conditions for which the proposed treatment, which has a rapid onset of action and ceases to act soon after it is discontinued, has shown promise in an open trial of therapy. The monitoring of treatment targets usually includes quantitative measurement of the patient''s symptoms with the use of simple patient diaries or questionnaires. Pairs of treatment periods are continued until effectiveness is proved or refuted. The cooperation of a pharmacy is required for the preparation of matching placebos and conduct of the trial. Formal statistical analysis may be helpful for interpreting the results. The practical approach presented in this paper allows clinicians to conduct their own N of 1 RCTs.     

Antidepressants versus placebo in major depression: an overview

Although the early antidepressant trials which included severely ill and hospitalized patients showed substantial drug‐placebo differences, these robust differences have not held up in the trials of the past couple of decades, whether sponsored by pharmaceutical companies or non‐profit agencies. This narrowing of the drug‐placebo difference has been attributed to a number of changes in the conduct of clinical trials. First, the advent of DSM‐III and the broadening of the definition of major depression have led to the inclusion of mildly to moderately ill patients into antidepressant trials. These patients may experience a smaller magnitude of antidepressant‐placebo differences. Second, drug development regulators, such as the U.S. Food and Drug Administration and the European Medicines Agency, have had a significant, albeit underappreciated, role in determining how modern antidepressant clinical trials are designed and conducted. Their concerns about possible false positive results have led to trial designs that are poor, difficult to conduct, and complicated to analyze. Attempts at better design and patient selection for antidepressant trials have not yielded the expected results. As of now, antidepressant clinical trials have an effect size of 0.30, which, although similar to the effects of treatments for many other chronic illnesses, such as hypertension, asthma and diabetes, is less than impressive.     

Treatment allocation for nonlinear models in clinical trials: the logistic model

Many clinical trials have a binary outcome variable. If covariate adjustment is necessary in the analysis, the logistic-regression model is frequently used. Optimal designs for allocating treatments for this model, or for any nonlinear or heteroscedastic model, are generally unbalanced with regard to overall treatment totals and totals within strata. However, all treatment-allocation methods that have been recommended for clinical trials in the literature are designed to balance treatments within strata, either directly or asymptotically. In this paper, the efficiencies of balanced sequential allocation schemes are measured relative to sequential Ds-optimal designs for the logistic model, using as examples completed trials conducted by the Eastern Cooperative Oncology Group and systematic simulations. The results demonstrate that stratified, balanced designs are quite efficient, in general. However, complete randomization is frequently inefficient, and will occasionally result in a trial that is very inefficient.     

Outcome measures in inflammatory rheumatic diseases

Inflammatory rheumatic diseases are generally multifaceted disorders and, therefore, measurement of multiple outcomes is relevant to most of these diseases. Developments in outcome measures in the rheumatic diseases are promoted by the development of successful treatments. Outcome measurement will increasingly deal with measurement of low levels of disease activity and avoidance of disease consequences. It is an advantage for patient management and knowledge transfer if the same outcomes are used in practice and in trials. Continuous measures of change are generally the most powerful and, therefore, are preferred as primary outcomes in trials. For daily clinical practice, outcome measures should reflect the patients' state and have to be easily derivable. The objective of this review is to describe recent developments in outcome measures for inflammatory rheumatic diseases for trials and clinical practice, with an emphasis on rheumatoid arthritis.