Economic endpoints in clinical trials

Healthcare decision makers are increasingly requesting information on the cost and cost-effectiveness of new medicines at the time of product launch. In order to provide this information, data on healthcare resource utilization and, in some cases, costs, may be collected in clinical trials. In this paper, we discuss some of the issues statisticians need to address when it is appropriate to include these economic endpoints in the trial. Several design issues are discussed, including the alternative types of and methods for collecting economic endpoint data, sample size and generalizability. Alternative approaches in the analysis of resource utilization, cost and cost-effectiveness are also presented. Finally, several of the analytic approaches are applied to actual data from a clinical trial.     

Surrogate endpoints for overall survival in advanced colorectal cancer: a clinician's perspective

Surrogate endpoints in oncology research and practice have garnered increasing attention over the past two decades. This activity has largely been driven by the promise surrogate endpoints appear to hold: the potential to get new therapies to seriously ill patients more rapidly. However, uncertainties abound. Even agreeing upon a definition of a "valid" surrogate endpoint has not been a straightforward exercise; this article begins by highlighting differences in how this term has been previously captured and applied, as well as laying out the basic criteria essential for its application in advanced colorectal cancer. Ideally, these elements include (but are not limited to) ease of measurement, rapid indication of treatment effect, and, most importantly, reliable and consistent prediction of the true impact of a treatment on the ultimate outcome of interest: overall survival. The strengths and weaknesses of current potential surrogate endpoints in advanced colorectal cancer, including performance status, carcinoembryonic antigen plasma level, overall response rate, time to progression, and disease-free survival, are each considered in turn. Finally, limitations of surrogate endpoints in the clinical setting, including challenges in extrapolation to new therapies, and the incomplete provision of information about potential adverse effects, are discussed. Work remains to be done between physicians and statisticians to bridge the gap between that which is statistically demonstrable and that which will be clinically useful.The term ;surrogate endpoint' was virtually unknown by most oncologists 15 years ago. A search in PubMed [http://www.ncbi.nlm.nih.gov] based on the words ;surrogate and cancer' shows that more than 2000 papers were published in medical journals in the last 20 years, with a dramatic increase of interest in the last five years. Interestingly, the same trend is observed when the words ;surrogate and heart' are entered into PubMed, suggesting that the issue of surrogate endpoints goes beyond the field of oncology, although the frequency of discussion varies (Figure 1; note different y-axis scales for oncology and cardiology).The goal of the present paper is to discuss the main issues surrounding surrogate endpoints from a clinician's point of view, using as an example surrogate endpoints of overall survival (OS) in advanced colorectal cancer (ACC).     

Surrogate endpoints for overall survival in early colorectal cancer from the clinician's perspective

The administration of adjuvant chemotherapy after resection of stage III colon cancer to prolong disease-free survival (DFS) and increase overall survival (OS) has been clinical standard since the early 1990s. Recently, 3-year DFS was recognized as surrogate endpoint for OS based on a meta-analysis of trials utilizing 5-fluorouracil as only active chemotherapy component. The standard of care in adjuvant therapy, however, has moved on to modern combination regimens including oxaliplatin, and novel targeted agents such as angiogenesis inhibitors and antibodies against epidermal growth factor receptor are currently undergoing rigorous testing in phase III adjuvant trials. For the practicing clinician, the use of surrogate endpoints to appreciate the efficacy of a specific adjuvant therapy contains various challenges, in particular, in discussions with patients. It is questionable whether 3-year DFS can still be considered an appropriate predictor of OS in complex clinical scenarios with continuous change in treatment standards in the adjuvant and palliative situation. Thus, the practicing oncologist needs to be aware of the limitations in the definition of surrogate endpoints in the adjuvant setting.     

Bayesian bandits in clinical trials

Suppose two treatments with binary responses are available for patients with some disease. Sequential allocation rules based on the theory of Bayesian bandit processes are examined. The patient horizon is assumed to be random and the objective is to maximize the total expected number of successes. This problem is equivalent to the classical two—armed bandit problem if we assume that the only information acquired during the trial about the patient horizon is whether or not it has so far been reached. When one treatment has a known success rate, the optimal allocation rule may sometimes be expressed in terms of dynamic allocation indices. The calculation of the indices is discussed, and in particular error bounds for the accuracy of the calculation are given in terms of the starting point of the backward induction process. When both treatments have unknown success rates the use of dynamic allocation indices with geometric discounting is suggested. Simulation results indicate that this rule works well even when the distribution of the number of the patients is not geometrical, and that the choice of the discount factor is also not crucial.     

Multicentre trials: a US regulatory perspective

Multicentre trials are very common in the field of drug development. In recent years, multicentre trials have taken on a multinational and multiregional aspect. We provide a conceptual framework for the use of multicentre trials in the context of drug development, from the perspective of drug regulation in the United States. In this paper, we review some regulatory history, milestones and standards as they relate to multicentre trials. Special attention is given to the similarities and differences in the approaches to multicentre trials in the following documents; Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug Applications, International Conference on Harmonization, Draft Guideline on Statistical Principles for clinical trials and the Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drug and Biologic Products. The paper includes a consideration of some of the issues in the analysis of data from multicentre trials.     

Use of progression-free survival as a surrogate marker in oncology trials: some regulatory issues

There has been interest in using progression-free survival as a surrogate endpoint for overall survival in oncology clinical trials. In order to objectively define this endpoint, clear understanding of what progression means, how it is measured and what its implications are need to be discussed. This article discusses some regulatory aspects of using progression-free survival as an endpoint.     

On improving research methodology in clinical trials

Research plays a vital role within biomedicine. Scientifically appropriate research provides a basis for appropriate medical decisions; conversely, inappropriate research may lead to flawed ;best medical practices' which, when followed, contribute to avoidable morbidity and mortality. Although an all-encompassing definition of ;appropriate medical research' is beyond the scope of this article, the concept clearly entails (among other things) that research methods be continually revised and updated as better methods become available. Despite the advent of evidence-based medicine, many research methods have become ;standard' even though there are legitimate scientific reasons to question the conclusions reached by such methods. We first illustrate prominent examples of inappropriate (yet regimented) research methods that are in widespread use. Second, as a way to improve the situation, we suggest a model of research that relies on standardized statistical analyses that individual researchers must consider as a default, but are free to challenge when they can marshal sufficient scientific evidence to demonstrate that the challenge is warranted. Third, we characterize the current system as analogous to ;unnatural selection' in the biological world and argue that our proposed model of research will enable ;natural' to replace ;unnatural' selection in the choice of research methodologies. Given the pervasiveness of inappropriate research methods, we believe that there are strong scientific and ethical reasons to create such a system, that, if properly designed, will both facilitate creativity and ensure methodological rigor while protecting the public at large from the threats posed by poor medical treatment decisions resulting from flawed research methodology.     

Two simple approaches for validating a binary surrogate endpoint using data from multiple trials

A surrogate endpoint is an endpoint that is observed before a true endpoint and is used to draw conclusions about the effect of intervention on true endpoint. To gauge confidence in the use of a surrogate endpoint, it must be validated. Two simple validation methods using data from multiple trials with surrogate and true endpoints are discussed: an estimation method extending previous work and new method based on hypothesis tests. The validation methods were applied to two data sets, each involving 10 randomized trials: one for patients with early colon cancer where the true endpoint was survival status at eight years and surrogate endpoint was cancer recurrence status at three years, and one for patients with advanced colorectal cancer where the true endpoint was survival status at 12 months and the surrogate endpoint was cancer recurrence status at six months. The estimation method uses the surrogate endpoint in the new trial and a model relating surrogate and true endpoints in previous trials to predict the effect of intervention on true endpoint in the new trial. For validation, each trial was successively treated as the ;new' trial and a comparison was made between predicted and observed effects of intervention on true endpoint. Performance of the surrogate endpoint was good in both data sets. The hypothesis testing method involves the z-statistic for the surrogate endpoint, which is the estimated effect of intervention on surrogate endpoint divided by its standard error. To use this z-statistic to test a null hypothesis of no effect of intervention on true endpoint, the critical value is increased above a standard level of 1.96 to a level determined by the relationships between surrogate and true endpoints in the data sets. This elevated critical value could be used for accelerated approval.     

三氯新在含漱液中的作用机理与临床试验研究

三氯新是众所周知的广泛应用的一种抗菌药物,最近被用于含漱液中。含有三氯新的含漱液的抑制菌斑和龈炎的作用已经由临床试验所证实。从三氯新的理化性质和药理作用、安全性和稳定性,从三氯新控制菌斑、改善牙周健康状况、与常规刷牙协同和对特殊人群的使用等方面,论述了国内外学者对三氯新在含漱液中的作用机理和临床试验研究,为我国含漱液的技术革新提供了有益的参考。     

HCV疫苗临床试验的研究进展

丙型肝炎病毒(hepatitis C virus,HCV)感染可引起慢性肝炎,最终导致肝衰竭、肝硬化和肝癌。目前尚无有效的HCV疫苗,其治疗仍以标准化方案聚乙二醇干扰素联合利巴韦林为主。其疗程长,费用高,副作用大,且不能从根本上解决慢性尤其是难治性丙肝的治疗难题,因此,HCV疫苗的研究迫在眉睫。本文就HCV疫苗临床试验的研究进展作一综述。     

Industrial-scale production trials for electrofused mullite refractory with controlled annealing

Conclusions The characteristics of the mullite investigated here are a lower content of fusing agents and good service properties. The results of trials prompt a recommendation to the effect that fused mullite refractories should be subjected to controlled annealing in compartment-type furnaces.Mullite refractory can be used with good effect in place of chamotte materials for the lining of thermal equipment.Translated from Ogneupory, No. 7, pp. 59–61, July, 1974.     

A perspective on non-stoichiometry in silicon carbide

The non-stoichiometric ceramics are amazing materials with potential to offer applications that are unachievable by using otherwise ideal stoichiometric counterparts. These materials have contributed in wide areas including superconductivity, optical, magnetic, electronic, structural, mechanical and transport applications. The deviation form stoichiometry in a large number of compounds, though usually avoided, has numerous benefits; by increasing ionic conductivity, offering band structure modifications, causing paramagnetic to ferromagnetic transitions, reducing magnetoresistance, increasing mechanical strength, enhancing electrochemical efficiency etc. Keeping in mind the promising contributions of silicon carbide among family of ceramic materials, this review highlights the implications of non-stoichiometry and its properties. The non-stoichiometry produced unintentionally or purposefully is strongly influenced by synthesis conditions and varies for silicon carbide grown in amorphous, crystalline, polycrystalline polytypes in the form of bulk, surfaces and low dimensional structures. The prospects of tuning the properties of silicon carbide on the basis of fabrication of silicon rich and carbon rich by monitoring silicon to carbon ratio are discussed in detail.     

Evaluating time to cancer recurrence as a surrogate marker for survival from an information theory perspective

The last two decades have seen a lot of development in the area of surrogate marker validation. One of these approaches places the evaluation in a meta-analytic framework, leading to definitions in terms of trial- and individual-level association. A drawback of this methodology is that different settings have led to different measures at the individual level. Using information theory, Alonso et al. proposed a unified framework, leading to a new definition of surrogacy, which offers interpretational advantages and is applicable in a wide range of situations. In this work, we illustrate how this information-theoretic approach can be used to evaluate surrogacy when both endpoints are of a time-to-event type. Two meta-analyses, in early and advanced colon cancer, respectively, are then used to evaluate the performance of time to cancer recurrence as a surrogate for overall survival.     

Statistical methods for HIV dynamic studies in AIDS clinical trials

Studies of HIV dynamics in AIDS research are very important for understanding pathogenesis of HIV infection and for assessing the potency of antiviral therapies. Since the viral dynamic results from clinical data were first published by Ho et al. and Wei et al., the study of HIV-1 dynamics in vivo has drawn a great attention from AIDS clinicians and researchers. Although the important findings from HIV dynamic studies have been published in many prestigious scientific journals, statistical methods for estimating viral dynamic parameters have not been paid enough attention by HIV dynamic investigators. The estimation methods in many viral dynamic studies are very crude and inefficient. In this paper, we review the statistical methods and mathematical models for HIV dynamic data analysis developed in recent years. We also address some practical issues and share our experiences in the design and analysis of viral dynamic studies. Some principles and guidelines for the design and analysis of viral dynamic studies are provided. The methodologies reviewed in this paper are also applicable to studies of other viruses such as hepatitis B virus or hepatitis C virus. We also pose some challenging statistical problems in this area in order to stimulate further study by the statistical research community.     

Placebos that harm: sham surgery controls in clinical trials

Recent debates over the use of sham surgery as a control for studies of fetal tissue transplantation for Parkinson's disease have focused primarily on rival interpretations of the US federal regulations governing human-subjects research. Using the core ethical and methodological considerations that underwrite the equipoise requirement, we find strong prima facie reasons against using sham surgery as a control in studies of cellular-based therapies for Parkinson's disease and more broadly in clinical research. Additionally, we believe that these reasons can be generalized to apply to the use of other placebo controls that carry significant risks of positive harms in and of themselves. As a result, our arguments are centrally relevant to the emerging drive to subject therapies with a surgical component to the same rigorous standards of evaluation as those governing the approval of new pharmaceuticals.     

An overview of group sequential methods in longitudinal clinical trials

During the last decade, several papers have been published on group sequential methods in general and on sequential longitudinal clinical trials in particular. This paper gives an overview of the proposed methods, emphasizing longitudinal clinical trials. Furthermore, it tries to answer some practical questions that may arise during the conduct of interim analyses in longitudinal trials. Simulations have been carried out to obtain insight in these practical considerations.     

Group sequential testing in dental clinical trials with longitudinal data on multiple outcome variables

In this article, methods are proposed for design and analysis of clinical trials that gather longitudinal data on multiple outcome variables. A valid test of the null hypothesis of no treatment group differences can be obtained for any choice of a working alternative hypothesis and a working covariance matrix for the outcome variables. Increased power can be achieved by accurate modeling of the true treatment effect and covariance structure. Implementation of the procedure is simple using existing software for generalized estimating equations. The procedure is an extension of the 'derived variable' technique (univariate analysis applied to a linear combination of the outcome variables) and also of O'Brien's generalized least squares test. The procedure is extended to allow sequential testing using an arbitrary division of the total type I error rate among repeated hypothesis tests. The methods are illustrated by the design of a study on the safety of dental amalgam fillings, which served as the motivation for the research.