In the era of systematic reviews, does the size of an individual trial still matter

BACKGROUND TO THE DEBATE: Systematic reviews that combine high-quality evidence from several trials are now widely considered to be at the top of the hierarchy of clinical evidence. Given the primacy of systematic reviews-and the fact that individual clinical trials rarely provide definitive answers to a clinical research question-some commentators question whether the sample size calculation for an individual trial still matters. Others point out that small trials can still be potentially misleading.     

The placebo response in clinical trials: more questions than answers

Meta-analyses and re-analyses of trial data have not been able to answer some of the essential questions that would allow prediction of placebo responses in clinical trials. We will confront these questions with current empirical evidence. The most important question asks whether the placebo response rates in the drug arm and in the placebo arm are equal. This 'additive model' is a general assumption in almost all placebo-controlled drug trials but has rarely been tested. Secondly, we would like to address whether the placebo response is a function of the likelihood of receiving drug/placebo. Evidence suggests that the number of study arms in a trial may determine the size of the placebo and the drug response. Thirdly, we ask what the size of the placebo response is in 'comparator' studies with a direct comparison of a (novel) drug against another drug. Meta-analytic and experimental evidence suggests that comparator studies may produce higher placebo response rates when compared with placebo-controlled trials. Finally, we address the placebo response rate outside the laboratory and outside of trials in clinical routine. This question poses a serious challenge whether the drug response in trials can be taken as evidence of drug effects in clinical routine.     

Vagal stimulation for heart diseases: from animals to men. An example of translational cardiology

A significant series of experimental and clinical studies have demonstrated the close association between reduced vagal reflexes (baroreflex sensitivity, BRS) and increased sudden and non-sudden cardiovascular mortality. Subsequently, evidence was provided that, also among chronic heart failure (HF) patients, depressed BRS is associated with a poorer outcome. At the same time, the encouraging results with experimental and clinical attempts to increase cardiac vagal activity led to a few experimental studies with vagal stimulation (VS) in different models for HF. We first performed a pilot study for VS in HF patients, and then in 2011 we reported the results of a small size multicentre clinical trial. The 6-month and 1-year results are encouraging for feasibility, safety and appear to have a favourable clinical effect. An ongoing large clinical trial will provide a definitive assessment of the efficacy and usefulness of chronic VS in HF patients.     

Poliomyelitis vaccine; epidemiologic observations on the safety and effectiveness in California in 1955

An independent clinical trial of the Penn seroflocculation test for cancer was carried out in order to learn whether this test might be clinically useful either in differential diagnosis or as a screening test for the detection of cancer. In addition, studies were made of the flocculation titer of sera giving positive Penn tests. Incidental observations were made concerning the reproducibility of the test. The trial provided no evidence that the test might be useful in cancer detection. The test should be improved technologically before further clinical evaluations are undertaken. Further study of the basic mechanisms that bring about the positive Penn reaction appears desirable.     

Evidence based general practice: a retrospective study of interventions in one training practice.

OBJECTIVES--To estimate the proportion of interventions in general practice that are based on evidence from clinical trials and to assess the appropriateness of such an evaluation. DESIGN--Retrospective review of case notes. SETTING--One suburban training general practice. SUBJECTS--122 consecutive doctor-patient consultations over two days. MAIN OUTCOME MEASURES--Proportions of interventions based on randomised controlled trials (from literature search with Medline, pharmaceutical databases, and standard textbooks), on convincing non-experimental evidence, and without substantial evidence. RESULTS--21 of the 122 consultations recorded were excluded due to insufficient data; 31 of the interventions were based on randomised controlled trial evidence and 51 based on convincing non-experimental evidence. Hence 82/101 (81%) of interventions were based on evidence meeting our criteria. CONCLUSIONS--Most interventions within general practice are based on evidence from clinical trials, but the methods used in such trials may not be the most appropriate to apply to this setting.     

Predictive probability early termination plans for phase II clinical trials

A phase II clinical trial is designed to gather data to help decide whether an experimental treatment has sufficient effectiveness to justify further study. In a one-arm trial with dichotomous outcome, we wish to test a simple null hypothesis on the Bernoulli parameter against a one-sided alternative in a sample of N patients. It is advisable to have a rule to terminate the trial early when evidence accumulates that the treatment is ineffective. Predictive probabilities based on the binomial distribution and beta and uniform prior distributions for the binomial parameter are found to be useful as the basis of group sequential designs. Size, power and average sample size for these designs are discussed. A process for the specification of an early termination plan, advice on the quantification of prior beliefs, and illustrative examples are included.     

From type 2 diabetes to antioxidant activity: a systematic review of the safety and efficacy of common and cassia cinnamon bark

Common (Cinnamomum verum, C. zeylanicum) and cassia (C. aromaticum) cinnamon have a long history of use as spices and flavouring agents. A number of pharmacological and clinical effects have been observed with their use. The objective of this study was to systematically review the scientific literature for preclinical and clinical evidence of safety, efficacy, and pharmacological activity of common and cassia cinnamon. Using the principles of evidence-based practice, we searched 9 electronic databases and compiled data according to the grade of evidence found. One pharmacological study on antioxidant activity and 7 clinical studies on various medical conditions were reported in the scientific literature including type 2 diabetes (3), Helicobacter pylori infection (1), activation of olfactory cortex of the brain (1), oral candidiasis in HIV (1), and chronic salmonellosis (1). Two of 3 randomized clinical trials on type 2 diabetes provided strong scientific evidence that cassia cinnamon demonstrates a therapeutic effect in reducing fasting blood glucose by 10.3%-29%; the third clinical trial did not observe this effect. Cassia cinnamon, however, did not have an effect at lowering glycosylated hemoglobin (HbA1c). One randomized clinical trial reported that cassia cinnamon lowered total cholesterol, low-density lipoprotein cholesterol, and triglycerides; the other 2 trials, however, did not observe this effect. There was good scientific evidence that a species of cinnamon was not effective at eradicating H. pylori infection. Common cinnamon showed weak to very weak evidence of efficacy in treating oral candidiasis in HIV patients and chronic salmonellosis.     

Embryonic stem cells: are useful in clinic treatments?

It is not uncommon to find statements in the social media and even in some scientific journals declaring that embryonic stem cells can be used in human medicine for therapeutic purposes. In our opinion, this statement does not fit the medical reality. To go into this subject in depth, and if possible to clarify it, we reviewed the most recent literature on clinical trials conducted with embryonic stem cells, concluding that up to the present time, there is only one ongoing clinical trial being carried out with these types of cells to treat a small group of patients with spinal cord injury. The results of this trial have still not been published. In conclusion, at present, there is only evidence of one phase I clinical trial conducted with embryonic stem cells, in comparison to the numerous trials conducted with adult stem cells.     

Systematic Evaluation of the Patient-Reported Outcome (PRO) Content of Clinical Trial Protocols

Background

Qualitative evidence suggests patient-reported outcome (PRO) information is frequently absent from clinical trial protocols, potentially leading to inconsistent PRO data collection and risking bias. Direct evidence regarding PRO trial protocol content is lacking. The aim of this study was to systematically evaluate the PRO-specific content of UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme trial protocols.

Methods and Findings

We conducted an electronic search of the NIHR HTA programme database (inception to August 2013) for protocols describing a randomised controlled trial including a primary/secondary PRO. Two investigators independently reviewed the content of each protocol, using a specially constructed PRO-specific protocol checklist, alongside the ‘Standard Protocol Items: Recommendations for Interventional Trials’ (SPIRIT) checklist. Disagreements were resolved through discussion with a third investigator. 75 trial protocols were included in the analysis. Protocols included a mean of 32/51 (63%) SPIRIT recommendations (range 16–41, SD 5.62) and 11/33 (33%) PRO-specific items (range 4–18, SD 3.56). Over half (61%) of the PRO items were incomplete. Protocols containing a primary PRO included slightly more PRO checklist items (mean 14/33 (43%)). PRO protocol content was not associated with general protocol completeness; thus, protocols judged as relatively ‘complete’ using SPIRIT were still likely to have omitted a large proportion of PRO checklist items.

Conclusions

The PRO components of HTA clinical trial protocols require improvement. Information on the PRO rationale/hypothesis, data collection methods, training and management was often absent. This low compliance is unsurprising; evidence shows existing PRO guidance for protocol developers remains difficult to access and lacks consistency. Study findings suggest there are a number of PRO protocol checklist items that are not fully addressed by the current SPIRIT statement. We therefore advocate the development of consensus-based supplementary guidelines, aimed at improving the completeness and quality of PRO content in clinical trial protocols.     

Organization of Clinical Trial on National Scale: Management of Early Cancer of the Breast

From a study of the organization of a national clinical trial on the management of early cancer of the breast in women there appear to be overwhelming advantages in studying large numbers of patients. To this end centres abroad have been encouraged to join. All the evidence at present suggests that it is feasible to organize a study on this scale, that the documentation and follow-up are accurate, and that the enthusiasm of the participants can be successfully fostered and maintained.     

Ram epididymitis: A clinical report

Two hundred and five ram lambs originating from several sources were assembled for a ram performance trial. All rams were immunized with a commercial Brucella ovis bacterin. Four rams developed clinical evidence of epididymitis during the 150 day trial. Actinobacillus seminis was identified as the causative agent.     

What is the future of CCR5 antagonists in rheumatoid arthritis?

A clinical trial of lupus patients with nephritis was established to determine any possible role for Atacicept, a biologic drug that blocks two B-cell-activating factors (BLyS and APRIL). The trial was stopped after just six patients had been enrolled because three patients developed serious infections. Initial concerns that the biologic was the main cause of the increased susceptibility to these infections have had to be revised on close inspection of the data. The evidence clearly points to a previously unrecognised capacity for mycophenolate to cause notable drops in immunoglobulin levels as the prime suspect.     

The promise and perils of stem cell therapeutics

Stem cells are the seeds of tissue repair and regeneration and a promising source for novel therapies. However, apart from hematopoietic stem cell (HSC) transplantation, essentially all other stem cell treatments remain experimental. High hopes have inspired numerous clinical trials, but it has been difficult to obtain unequivocal evidence for robust clinical benefit. In recent years, unproven therapies have been widely practiced outside the standard clinical trial network, threatening the cause of legitimate clinical investigation. Numerous challenges and technical barriers must be overcome before novel stem cell therapies can achieve meaningful clinical impact.     

Helicobacter pylori public health implications

Population Helicobacter pylori screening and treatment has the potential to dramatically reduce global gastric cancer mortality. There is overwhelming evidence that the infection is a major cause of distal gastric adenocarcinoma. There is also randomized controlled trial evidence that H. pylori eradication reverses or ameliorates histological changes in the gastric mucosa that are important in carcinogenesis. Preliminary randomized controlled trial data suggest that screening and treatment may reduce the risk of gastric cancer although the number of cancer cases was small. Population H. pylori screening and treatment will also reduce mortality from peptic ulcer complications and reduce the burden of dyspepsia in the community. The reduction in health service dyspepsia costs means that this could be the first programme to pay for itself. From a scientific perspective, we still have insufficient evidence to conclude the benefits of population H. pylori screening are greater than the possible harms and we need more randomized controlled trial data. From a public health perspective however, sometimes screening programmes are developed with imperfect information. The medical community should be consistent and if we are instituting other population screening programmes without randomized controlled trial evidence then H. pylori testing and treatment should also be considered.     

Elastic priors to dynamically borrow information from historical data in clinical trials

Use of historical data and real-world evidence holds great potential to improve the efficiency of clinical trials. One major challenge is to effectively borrow information from historical data while maintaining a reasonable type I error and minimal bias. We propose the elastic prior approach to address this challenge. Unlike existing approaches, this approach proactively controls the behavior of information borrowing and type I errors by incorporating a well-known concept of clinically significant difference through an elastic function, defined as a monotonic function of a congruence measure between historical data and trial data. The elastic function is constructed to satisfy a set of prespecified criteria such that the resulting prior will strongly borrow information when historical and trial data are congruent, but refrain from information borrowing when historical and trial data are incongruent. The elastic prior approach has a desirable property of being information borrowing consistent, that is, asymptotically controls type I error at the nominal value, no matter that historical data are congruent or not to the trial data. Our simulation study that evaluates the finite sample characteristic confirms that, compared to existing methods, the elastic prior has better type I error control and yields competitive or higher power. The proposed approach is applicable to binary, continuous, and survival endpoints.     

A novel approach to reducing disparities in health outcomes by enhancing interpretation of cancer clinical trials for underrepresented patient groups

There has been a growing realization, based on emerging evidence from the point of care, that real-world outcomes of patients with cancer are often inferior to those reported in conventional clinical trials. This phenomenon can be attributed in part to deficits in external validity that are present in many studies. Several factors contribute to external validity deficits, including: narrow eligibility criteria; differences between protocol-specified procedures and routine care; and inadequate access to clinical trial participation among underrepresented and socioeconomically disadvantaged groups. As a result, the current body of clinical evidence derived from conventional clinical trials can be inadequate to inform patient-specific treatment decisions at the point of care. Furthermore, lack of practical guidance on how to evaluate the impact of external validity deficits can impede both the design of more generalizable clinical trials and efforts to personalize treatment decisions for individual patients. In this methodological review, we suggest an approach to aid clinicians in such evaluations, providing visual and quantitative methods for assessing the magnitude of, and adjusting for, the impact of external validity deficits in conventional clinical trials. Our methods and visualizations have broad applicability across important areas of real-world medical decision-making and research, providing opportunities to design clinical studies that are more reflective of the diverse needs of patients with cancer, including those excluded from traditional clinical trials due to narrow eligibility criteria, socioeconomic disadvantages, and other systemic barriers to equitable access to healthcare resources.     

National cholesterol education program keeps a priority on lifestyle modification to decrease cardiovascular disease risk.

The National Cholesterol Education Program's updated third Adult Treatment Panel report on clinical guidelines for cholesterol testing and management adds to the base of knowledge provided by two previous Adult Treatment Panel reports. Similar to the other reports, it has distinctive features and goals that are in accord with the most currently available clinical trial evidence. The major new feature of the third report is a focus on primary prevention of coronary heart disease in persons with multiple coronary heart disease risk factors. The guidelines provide the rationale for intensive cholesterol-lowering therapy in clinical management, and they provide detailed information to help inform clinical judgment for implementation of both medical nutrition management (therapeutic lifestyle changes) and drug therapy for treatment of high blood cholesterol.     

A New Framework for Interpreting the Outcomes of Imperfectly Blinded Controlled Clinical Trials

It is well known that the outcome of an intervention is affected both by the inherent effects of the intervention and the patient''s expectations. For this reason in comparative clinical trials an effort is made to conceal the nature of the administered intervention from the participants in the trial i.e. to blind the trial. Yet, in practice perfect blinding is impossible to ensure or even verify post hoc. The current clinical standard is to follow up the trial with an auxiliary questionnaire, which allows trial participants to express in closed form their belief concerning the intervention, i.e. trial group assignment (treatment or control). Auxiliary questionnaire responses are then used to compute the extent of blinding in the trial in the form of a blinding index. If the estimated extent of blinding exceeds a particular threshold the trial is deemed sufficiently blinded; otherwise, the strength of evidence of the trial is brought into question. This may necessitate that the trial is repeated. In this paper we make several contributions. Firstly, we identify a series of problems of the aforesaid clinical practice and discuss them in context of the most commonly used blinding indexes. Secondly, we formulate a novel approach for handling imperfectly blinded trials. We adopt a feedback questionnaire of the same form as that which is currently in use, but interpret the collected data using a novel statistical method, significantly different from that proposed in the previous work. Unlike the previously proposed approaches, our method is void of any ad hoc free parameters and robust to small changes in the participants'' feedback responses. Our method also does not discard any data and is not predicated on any strong assumptions used to interpret participants'' feedback. The key idea behind the present method is that it is meaningful to compare only the corresponding treatment and control participant sub-groups, that is, sub-groups matched by their auxiliary responses. A series of experiments on simulated trials is used to demonstrate the effectiveness of the proposed approach and its superiority over those currently in use.     

The use of eicosapentaenoic acid in the treatment of chronic fatigue syndrome

There is evidence that there is an association between chronic fatigue syndrome, a condition of unknown aetiology, and essential fatty acids. This evidence is based on the actions of essential fatty acids, the results of proton neurospectroscopy studies, and essential fatty acid trial data. A series of patients with chronic fatigue syndrome were treated solely with a high-eicosapentaenoic acid-containing essential fatty acid supplement. All showed improvement in their symptomatology within eight to 12 weeks. These results, which are consistent with a recent detailed report of cerebral and clinical changes associated with a high intake of eicosapentaenoic acid, suggest that this n-3 highly unsaturated fatty acid may offer the hope of effective treatment for at least some patients with chronic fatigue syndrome.     

Pre-clinical evidence of a dual NADPH oxidase 1/4 inhibitor (setanaxib) in liver,kidney and lung fibrosis

Fibrosis describes a dysregulated tissue remodelling response to persistent cellular injury and is the final pathological consequence of many chronic diseases that affect the liver, kidney and lung. Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) enzymes produce reactive oxygen species (ROS) as their primary function. ROS derived from NOX1 and NOX4 are key mediators of liver, kidney and lung fibrosis. Setanaxib (GKT137831) is a first-in-class, dual inhibitor of NOX1/4 and is the first NOX inhibitor to progress to clinical trial investigation. The anti-fibrotic effects of setanaxib in liver, kidney and lung fibrosis are supported by multiple lines of pre-clinical evidence. However, despite advances in our understanding, the precise roles of NOX1/4 in fibrosis require further investigation. Additionally, there is a translational gap between the pre-clinical observations of setanaxib to date and the applicability of these to human patients within a clinical setting. This narrative review critically examines the role of NOX1/4 in liver, kidney and lung fibrosis, alongside the available evidence investigating setanaxib as a therapeutic agent in pre-clinical models of disease. We discuss the potential clinical translatability of this pre-clinical evidence, which provides rationale to explore NOX1/4 inhibition by setanaxib across various fibrotic pathologies in clinical trials involving human patients.