Evaluation of interventions

The first modern randomized controlled trial was published in 1948, and featured randomly allocated treatment groups, blinded outcome assessment, and a sufficient number of patients. Randomized controlled trials are now accepted as the best possible way to assess the effects of clinical interventions, but good trials sometimes disagree. Although the elements of a credible trial have been defined, the relative importance of these elements to results is not known. Information from clinical trials may be difficult to use in the care of patients if trial outcomes are not patient centered or the conditions of the trial are very different from the situation in clinical practice. Observational studies are often, but not always, an adequate substitute from randomized trials. Systematic reviews with meta-analyses may reveal patterns of results when individual trials do not, and so complement the information content of large trials. When trials disagree, resolution may be found not by from more trials but also from critical appraisal of individual trials, weighing the totality of the evidence, and Bayesian reasoning.     

Evaluating the interaction between the therapy and the treatment in clinical trials by the propensity score weighting method

In clinical trials for antihypertensive drugs, a combination therapy trial and a monotherapy trial are often conducted simultaneously. In this situation, it can be a clinical concern to know the difference of the safety or efficacy of the new drug between the two therapies, in other words, to investigate the interaction between the therapy (monotherapy or combination therapy) and the treatment (test or control). However, because patients are often registered in either of these trials on the basis of their background characteristics, specific patients may be selected to participate in the monotherapy trial or combination therapy trial and not chosen at random, whereas the treatment is assigned randomly in each trial after registration. If this fact is not considered, the statistical analysis of the interaction may be biased. In this paper, we aim to evaluate the interaction between the two aforementioned factors by adjusting for covariates that may affect registration in the two trials. For this purpose, we apply the propensity score weighting method to suit the problem. The propensity score in this case is decomposed into the usual propensity score for the registration and the assignment probability for the random treatment assignment on the basis of their two-stage structure. We also discuss the augmented estimator known as the doubly robust estimator. In addition, we apply this method to data of a clinical trial for an antihypertensive drug that was conducted in Japan and conduct a simulation study to evaluate the performance of our proposed method.     

Experiences with the first, Hungarian autologous bone marrow cell transplantation in acute myocardial infarction

Intracoronary transfer of autologous bone marrow cells promotes recovery of left ventricular systolic function in patients with acute myocardial infarction. Although the exact mechanisms of stem cell therapy are still intensely debated, the concept of stem cell therapy has already been introduced into the clinical practice--at least as an adjunctive therapy in clinical trials. In this article the authors report their experiences about the first Hungarian phase I. trial in bone marrow stem cell transplantation after acute myocardial infarction. So far, four patients with acute ST elevation myocardial infarction were eligible and recruited into the trial. All patients received purified, autologous bone marrow stem cells into the re-opened infarct related artery via a second catheterisation. The primary end point of the study is ejection fraction, which is measured by cardiac MRI at the beginning and 6 months after recruitment. So far, cell transfer did not increase the risk of adverse clinical events or proarrhythmic effects.     

Drug treatment trials in hypertension: a review

Thirteen controlled clinical trials (11 randomized) reporting morbidity and mortality results during 1960-1982 are summarized. Given the diverse design features, results are presented both for individual trials and for several combinations of similar studies, to provide more stable estimates of effects. Two of three trials in severe hypertension, while lacking enough events to evaluate effect on mortality, found significant reductions in "hypertensive" events, with the overall estimate being an 80% reduction. Similarly, combining six trials in less severe hypertension with untreated controls showed a 54% reduction in such events. The favorable trend in all-causes mortality from these trial results, whether viewed separately or in combination, was not significant. However, the findings from a large randomized trial with community controls, the Hypertension Detection and Follow-up Program, indicated significant reduction of all-causes mortality, the magnitude of which was consistent with the other trials. Outcomes of hypertensive participants in the Multiple Risk Factor Intervention Trial raised questions about mortality benefits in certain subgroups. These and other issues about patient benefit are further addressed with trial data and reference to the 1984 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. We note also 1) that evidence for reduction of coronary heart disease death or nonfatal myocardial infarction with antihypertensive drug treatment is weak, perhaps due to inadequate power to detect such a difference, and that data are limited regarding effects on quality of life. Nevertheless, the overall trial results provide strong support for drug treatment of severe hypertension, and for most individuals with less severe hypertension, when nonpharmacologic treatment will not suffice.     

Clinical drug trials in general practice: how well are external validity issues reported?

Background

When reading a report of a clinical trial, it should be possible to judge whether the results are relevant for your patients. Issues affecting the external validity or generalizability of a trial should therefore be reported. Our aim was to determine whether articles with published results from a complete cohort of drug trials conducted entirely or partly in general practice reported sufficient information about the trials to consider the external validity.

Methods

A cohort of 196 drug trials in Norwegian general practice was previously identified from the Norwegian Medicines Agency archive with year of application for approval 1998–2007. After comprehensive literature searches, 134 journal articles reporting results published from 2000 to 2015 were identified. In these articles, we considered the reporting of the following issues relevant for external validity: reporting of the clinical setting; selection of patients before inclusion in a trial; reporting of patients’ co-morbidity, co-medication or ethnicity; choice of primary outcome; and reporting of adverse events.

Results

Of these 134 articles, only 30 (22%) reported the clinical setting of the trial. The number of patients screened before enrolment was reported in 61 articles (46%). The primary outcome of the trial was a surrogate outcome for 60 trials (45%), a clinical outcome for 39 (29%) and a patient-reported outcome for 25 (19%). Clinical details of adverse events were reported in 124 (93%) articles. Co-morbidity of included participants was reported in 54 trials (40%), co-medication in 27 (20%) and race/ethnicity in 78 (58%).

Conclusions

The clinical setting of the trials, the selection of patients before enrolment, and co-morbidity or co-medication of participants was most commonly not reported, limiting the possibility to consider the generalizability of a trial. It may therefore be difficult for readers to judge whether drug trial results are applicable to clinical decision-making in general practice or when developing clinical guidelines.

     

公众对临床试验的认知、实践与态度的调查研究

目的评价公众的临床试验的认知、实践与态度。方法采用匿名的横断面在线调查,共收集702份18岁以上中国公众的有效调查问卷。结果在702名被调查者中,有84.2%听说过临床试验,但是仅有6.0%作为受试者参与过药物临床试验。83.6%的被调查者知道“受试者的隐私和个人信息应该得到充分保护”,仅48.4%的被调查者知道“患者也可以参与设计和发起符合自己需要的临床试验”。41.7%的被调查者“愿意作为志愿者参加临床试验”。回归分析表明“工作/专业领域”“是否作为受试者参与过药物临床试验”“是否有亲人朋友作为受试者参与过药物临床试验”是影响公众参与临床试验意愿的显著因素。结论公众对临床试验的认知程度尚可,但是对于以患者为中心的临床试验发展趋势认识较低。公众的临床试验参与意愿较低,并且受自身专业背景以及相关经历影响很大。有必要开展针对公众的临床试验科普活动,积极发展临床试验公益团体,提升公众临床试验认知水平和参与积极度。     

Reperfusion therapy for patients with an acute myocardial infarct with ST-segment elevation: fibrinolysis versus transport to a cardiac center for primary angioplasty

Although fibrinolytic therapy for acute myocardial infarction is widely used and can be administered prior to hospitalisation, it is only successful in restoring full early coronary patency in about 60% of patients and has a 0.5% to 1% risk of severe side effects. Primary percutaneous coronary angioplasty carried out as an alternative to fibrinolysis avoids the risk of fibrinolytic therapy and restores patency in nearly 90% of cases. Data from randomised trials of primary angioplasty versus fibrinolytic therapy in acute myocardial infarction reveal that angioplasty results in a significant reduction in mortality. Furthermore, primary angioplasty can be improved by means of a new pre-angioplasty drug therapy (so-called facilitated primary angioplasty). Transport to a cardiac centre for primary angioplasty (of which there are 14 in the Netherlands) is feasible and safe. Although the time to treatment is delayed by a further 90 minutes, it tends to save lives and prevent strokes and it also significantly reduces the incidence of reinfarction. Interestingly, the time gained to treatment with prehospital fibrinolytic therapy compared to in-hospital therapy gave an outcome similar to that found upon comparing transport and primary angioplasty. Rescue procedures (angioplasty) within 24 hours are necessary in about 30% of patients who are initially treated with lytic therapy. These results support prehospital triage for fibrinolysis or transport to a cardiac centre, where early angioplasty can be performed if clinically indicated. A trial to determine the policy of choice is at present being conducted in the Netherlands.     

Clinical trials designed to evaluate therapeutic preferences

We present an experimental design for the evaluation of therapeutic preferences among well established similar modes of therapy. The measure of the degree of preference is based on clinical decisions to continue or discontinue the current treatment at each patient visit. Such a trial simulates decision-making in ordinary clinical practice, while adhering to the scientific principles of experimental design, and it alleviates some of the ethical problems inherent in randomized allocation of a treatment for a period of fixed length in conventional controlled trials. We discuss the design and methods of analysis and illustrate their application with data from a trial comparing three alternative drug treatments for chronic asthma. Such clinical trials provide a mechanism for examining concordance between the relative efficacy of treatments predicted from conventional controlled clinical trials and their ultimate performance in ordinary clinical practice, expressed in terms of therapeutic preferences.     

Size isn't everything

Clinical trials now often involve thousands of patients, and statisticians emphasize the importance of trial size in ensuring that 'correct' answers are obtained. However, when a good treatment appears for a disease that was hitherto untreatable - for example, oranges for scurvy or streptomycin for tuberculosis - only a small trial is needed. Large trials are only needed to demonstrate small effects. The meta-analysis of small trials is often misleading, and may hide undesirable effects of individual drugs. The concept of equivalence between treatments is important, and while a statistically adequate equivalence trial may have to be very large, many clinicians will question the need for extreme statistical propriety. Clinical trials often do not reflect 'real world' practice, and the clinical relevance of a trial is more important than its size.     

Are randomized control trial outcomes influenced by the inclusion of a placebo group?: a systematic review of nonsteroidal antiinflammatory drug trials for arthritis treatment

Placebo groups are often included in randomized control trials evaluating drug therapy, yet we know little about the placebo effect. The purpose of our study was to evaluate how the presence of a placebo group in a randomized control trial (RCT) influences the patients' ratings of the efficacy of an active drug therapy and their reporting of its adverse effects. We identified studies published between 1966 and 1994 using MEDLINE. Randomized control trials evaluating acetylsalicylic acid, diclofenac, or indomethacin for the treatment of osteo or rheumatoid arthritis were included in our sample. Two investigators independently extracted data. Fifty-eight treatment arms met our inclusion criteria and were available for analysis. Twenty-five treatment arms evaluated a nonsteroidal antiinflammatory drug (NSAID) in placebo control trials and 33 in comparative trials. Using a logistic regression model to adjust for the differences between the evaluated drugs and between the types of arthritis, we found that patients receiving an NSAID in a placebo control trial were more likely to withdraw due to inefficacy (OR=1.3; 95% CI, 1.0 to 1.6; P=0.04). Using a similar model, withdrawals due to adverse effects were found to be more common when the NSAID was given in trials that did not include a placebo group (OR=1.5; 95% CI, 1.1 to 1.9; P=0.002) as were reports of cutaneous (OR=4.2; 95% CI, 1.7 to 9.9), gastrointestinal (OR=1.6; 95% CI, 1.3 to 2.0), and other types (OR=5.3; 95% CI, 3.8 to 7.4) of adverse effects. Although reports of central nervous system adverse effects were more frequent in the comparative trials, this difference was not significant. Including a placebo group in a RCT changes how patients rate the efficacy and adverse effects of their therapy. Our results highlight the need to consider the placebo effect in the design and analyses of clinical trials.     

A two-stage Bayesian design for co-development of new drugs and companion diagnostics

Most new drug development in oncology is based on targeting specific molecules. Genomic profiles and deregulated drug targets vary from patient to patient making new treatments likely to benefit only a subset of patients traditionally grouped in the same clinical trials. Predictive biomarkers are being developed to identify patients who are most likely to benefit from a particular treatment; however, their biological basis is not always conclusive. The inclusion of marker-negative patients in a trial is therefore sometimes necessary for a more informative evaluation of the therapy. In this paper, we present a two-stage Bayesian design that includes both marker-positive and marker-negative patients in a clinical trial. We formulate a family of prior distributions that represent the degree of a priori confidence in the predictive biomarker. To avoid exposing patients to a treatment to which they may not be expected to benefit, we perform an interim analysis that may stop accrual of marker-negative patients or accrual of all patients. We demonstrate with simulations that the design and priors used control type I errors, give adequate power, and enable the early futility analysis of test-negative patients to be based on prior specification on the strength of evidence in the biomarker.     

Aspirin and fibrinolysis in acute myocardial infarction: meta-analytic evidence for synergy.

A meta-analysis of randomized clinical trials of fibrinolysis was performed, examining the interaction between aspirin and fibrinolysis in treating patients with acute myocardial infarction. Reductions in the odds of death up to 35 days were assessed for patients receiving tissue plasminogen activator or streptokinase up to 6 hours after the onset of symptoms. No significant difference in effectiveness between tissue plasminogen activator and streptokinase was demonstrated. The overall reduction in odds of death due to fibrinolytic therapy was 28%. However, there was a significant difference between the odds reduction of 24% when fibrinolysis is compared to placebo, and 40% when fibrinolysis and aspirin combined are compared to aspirin alone (p = 0.02). This difference indicates that there exists a synergistic interaction between coronary fibrinolysis and aspirin rather than independence of their beneficial effects, as is generally believed. These results illustrate the perils of assessing drug efficacy, even in an overview of all relevant trials, without consideration of identifiable sources of heterogeneity such as the interaction between the treatment of interest and co-interventions. They also demonstrate the potential application of logistic regression diagnostic techniques to meta-analyses.     

MET抑制剂在晚期肝癌中的应用进展

目前晚期肝细胞癌的标准药物治疗是索拉菲尼,但其临床效果是有限的,而且副作用较大。但除索拉菲尼以外,在所有完成的Ⅲ期临床对照研究中,没有药物在作为一线或二线用药时能明显提高生存率。最近一项Ⅱ期随机对照研究结果的亚组分析显示,一种选择性MET抑制剂ARQ197,在全身治疗失败或不耐受全身治疗的伴有MET扩增的晚期肝细胞癌患者中应用,能明显提高总生存率。在本文中,我们对所有目前正在进行及已经完成临床试验的MET抑制剂做一综述。旨在进一步了解MET抑制剂在肝癌中的应用情况,为晚期肝癌的药物治疗提供新的策略。     

Is the successful eradication of Helicobacter pylori sufficient for the healing of peptic ulcer?

Helicobacter pylori has a major role in the pathogenesis of peptic ulcer disease. Cure of the infection is essential in ulcer healing, but an additional PPI therapy after completing eradication treatment is widespread in clinical practice. In the present work clinical studies evaluating peptic ulcer healing followed or not by PPI treatment after eradication therapy were analyzed. The results of these trials are concordant that only a minority of patients with duodenal ulcer would benefit from prolonged acid suppressive treatment, a successful eradication therapy (that counts for a large proportion) is sufficient. There are less data available concerning gastric ulcer: successful eradication is also essential to ulcer healing and to avoid relapse, however it seems that post-eradication PPI therapy might be beneficial.     

The use of putative placebo in active control trials: two applications in a regulatory setting

For life-threatening diseases, ethical considerations preclude the inclusion of an untreated control group in the investigation of a new therapeutic agent when a standard therapy exists. In these cases, active controlled studies are conducted, and may be planned to demonstrate either superiority or equivalence/non-inferiority of the new drug over the standard therapy (active control). In the non-inferiority study, an important aspect is the ability to detect an inferior drug (assay sensitivity). It has been suggested that assay sensitivity for a non-inferiority study should be deduced from historical data, specifically placebo controlled studies with the standard therapy. The assessment of assay sensitivity may also be important in a superiority trial that fails to demonstrate a statistically significant difference between treatments, and the sponsor attempts to determine whether there is lack of inferiority as an alternative hypothesis for regulatory approval. This paper describes two methods of putative placebo analysis for assessing assay sensitivity in active controlled trials. One approach imputes a point estimate for the odds ratio (95 per cent confidence interval) for a new drug (T) compared to a placebo control (P). A Bayesian approach calculates the posterior probability that T is superior to P, or, that T is at least k per cent as good as the active control (A) and A is more effective than P. These methods are applied in two clinical/regulatory settings: a phase III trial comparing docetaxel (Taxotere) to doxorubicin in metastatic breast cancer patients, and a phase III programme with two trials comparing enoxaparin (Lovenox) plus aspirin to unfractionated heparin plus aspirin in patients with unstable angina or non-Q-wave myocardial infarction. The methodologies presented in this paper were used in securing regulatory approval for docetaxel in the treatment of locally advanced or metastatic breast cancer after failure of prior chemotherapy, and for enoxaparin in the treatment of acute coronary syndrome.     

LONG-TERM FOLLOW-UP IN AIDS CLINICAL TRIALS

There are several different strategies for the follow-up of patients on AIDS clinical trials. In some trials, data are only collected until patients stop protocol therapy for any reason. Alternatively, patients are followed until they have disease progression or the study ends. It has been suggested in some trials that patients have data collected after they have stopped protocol therapy either because they reached a study endpoint or all patients on the trial have been switched to the superior therapy. The effect of these strategies on the conclusions that can be drawn from a trial will be described using simulations. To calculate the operating characteristics of a strategy that involves a primary and a secondary endpoint, it is necessary to formalize the notion that the results of a secondary analysis support or contradict the primary analysis.     

Durability of improvement achieved in a clinical trial. Is compliance an issue?

BACKGROUND: The effects seen in clinical trials may not translate to actual practice situations. We examined the persistence of blood pressure effects 31 months after a clinical trial of treatment with hypotensive agents. METHODS: Nineteen previously untreated middle-aged men with hypertension had their office and ambulatory blood pressure recorded after 4 weeks of placebo treatment, 4 weeks of active treatment in a clinical trial, and 31 months of treatment in clinical practice. All recording was done by the same physician (IE). RESULTS: Mean 24-hour blood pressure was 138/92 mm Hg after 4 weeks of placebo treatment, 128/85 mm Hg after 4 weeks of active treatment in the clinical trial, and 136/87 mm Hg after a mean of 31 months of treatment in clinical practice. The corresponding blood pressure values > or =140/90 mm Hg during the daytime were 47%, 24%, and 39%, and office blood pressures were 155/101, 145/93, and 150/91 mm Hg. Individual comparison revealed that 6 of the 19 patients had higher mean 24-hour blood pressure after several months of treatment in clinical practice than after 4 weeks of active treatment in the clinical trial. CONCLUSIONS: In our study, the significantly reduced blood pressure in the clinical trial did not persist when followed up in clinical practice. At follow-up, one third of the patients had blood pressure values similar to those before active treatment. The reason for this is unclear, but inconsistent compliance may play a part in the lack of durability of the improvements. Our results indicate that effects seen in short-term clinical trials may not translate to long-term benefits in clinical practice.     

Novel designs for multi-arm clinical trials with survival outcomes with an application in ovarian cancer

With the increasing pace of drug development, it is not unusual for several promising treatment regimens to be ready simultaneously for testing in a randomized phase III setting. Various limiting factors, including the time needed to transfer research results to clinical practice and a narrow 'window of opportunity', may make it unfeasible to perform trials to test such regimens sequentially against a control treatment in a traditional two-arm parallel group design. We present an approach to trial design based on eliminating inferior contenders at an early stage, allowing through to a second stage only treatments that show a predefined degree of advantage against a control treatment. The first stage of testing utilizes a marker known to be a valid intermediate outcome measure or surrogate for the definitive outcome. The experimental arms are compared pairwise with control according to this intermediate outcome measure. Arms that survive the comparison enter a second stage of patient accrual culminating in comparisons against control on the outcome measure of primary interest. We show how the design may be realized in practice by considering hypothetically distinct trials at stages 1 and 2, each with their own operating characteristics. The overall operating characteristics are computed from the stage 1 and 2 size and power and the correlation between the treatment effects on the intermediate and primary outcome measures according to a bivariate Normal approximation. The correlation is estimated by bootstrapping individual patient data from previous trials. We illustrate the general approach in a design of a real trial of four new chemotherapy regimens for advanced ovarian cancer. The intermediate outcome measure is progression-free survival. An international randomized controlled trial using the new design is already under way.     

Calcium channel blockers in diabetic subjects: innocent at last?

Calcium antagonists are indicted as a potential trigger of a variety of complications spanning from myocardial infarction to bleeding and cancer. Three randomised controlled trials, the MIDAS, the FACET and the ABCD trial, seem to suggest that the risk for myocardial infarction is increased in diabetics on calcium antagonists. These trials in aggregate totalled only 92 cardiovascular events and it is possible that the observed differences were due to random errors. Most of the patients of the ABCD trial discontinued the medication to which they were initially randomised before the end of the study, which raised the possibility of systematic bias. In both the MIDAS and ABCD studies cardiovascular events were secondary end-points and the apparent adverse effects were identified only by subgroup analyses. Furthermore, in both studies, patients in the control groups were being treated with ACE inhibitors. The lack of a placebo group makes it impossible to establish whether the observed effects were due to the harmful influence of calcium antagonism or to the favourable effects of ACE inhibition. New data abstracted from the PIUMA database show that the rate of total cardiovascular and cardiac events did not differ between diabetics on calcium antagonists and diabetics not using these drugs. These new data are in keeping with findings in the HOT study where an impressive degree of cardiac protection was observed in diabetic patients on felodipine.     

Monitoring a randomized clinical trial for futility: the north-Norwegian lidocaine intervention trial

Randomized clinical trials of acute disease are usually designed as single-look, fixed sample size trials. This methodological study compares the conventional approach with a multiple-look, group sequential design with stopping rules for both treatment efficacy and for an inconclusive trial outcome, called trial futility. An ongoing trial on pre-hospital prophylaxis of sudden death in acute myocardial infarction forms the basis of the analysis. The effects of introducing multiple looks (or interim analyses) and tests for futility were obtained by binomial simulation. The introduction of four looks (that is, three interim and a final analysis) resulted in a modest increase in the maximal number of patients required. This was, however, fully compensated for by the high probability of early termination in case of treatment efficacy. The addition of futility tests, enabling termination at half the maximum trial size when there is no treatment difference, resulted in only a negligible reduction of overall power. We conclude that multiple-look, group sequential designs testing for both treatment efficacy and trial futility may improve the cost-effectiveness of randomized trials of acute disease.