Abstract:
:Equivalence trials aim to show that two treatments have equivalent therapeutic effects. The approach is to define, in advance, a range of equivalence -d to +d for the treatment difference such that any value in the range is clinically unimportant. If the confidence interval for the difference, calculated after the trial, lies entirely within the interval, then equivalence is claimed. Glaxo Wellcome has carried out a series of trials using this methodology to assess new formulations of inhaled beta-agonists and inhaled steroids in asthma. Eleven of these trials are used to review some practical issues in equivalence trials. For the series of asthma trials, a range for peak expiratory flow rate (PEF) from -15 to +15 l/min was chosen to be the range of equivalence. This fitted well with physicians' opinions and with previously demonstrated differences between active and placebo. The choice of the size of the confidence interval should depend on the medical severity of the clinical endpoints under consideration and the level of risk acceptable in assuming equivalence if a difference of potential importance exists. From this point of view, a recommendation in the CPMP Note for Guidance on Biostatistics that 95 per cent confidence intervals should be used is inappropriate. Intent-to-treat (ITT) and per-protocol (PP) analyses were compared for the eleven asthma trials. Confidence intervals were always wider for the PP analysis and this was entirely due to the smaller number of subjects included in the PP analysis. There was no evidence that the ITT analyses were more conservative in their estimates of treatment difference. The need to demonstrate equivalence in both an ITT and a PP analysis in a regulatory trial increases the regulatory burden on drug developers. The relative importance of the two analyses will depend on the definitions used in particular therapeutic areas. Demonstrating equivalence in one population with strong support from the other would be preferred from the Industry viewpoint. In trials with regulatory importance, prior agreement with regulators on the role of ITT and PP populations should be sought. Trial designs will need to take account of the estimated size of the PP population if adequate power is needed for both analyses. Careful design in the series of asthma trials, particularly identifying a population of patients with potential to improve, resulted in notable increases in lung function during the course of the trials for both treatments. This provided reassurance that equivalence was not due to a lack of efficacy for both treatments. In one trial equivalence was demonstrated overall but a treatment by country interaction was noted. However, this interaction could not be attributed to differences in patient characteristics or baseline data between the countries. Study conduct was also similar in the different countries. The conclusion was that the interaction was spurious and that the trial provided good evidence of equivalence.
journal_name
Stat Medjournal_title
Statistics in medicineauthors
Ebbutt AF,Frith Ldoi
10.1002/(sici)1097-0258(19980815/30)17:15/16<1691:subject
Has Abstractpub_date
1998-08-15 00:00:00pages
1691-701issue
15-16eissn
0277-6715issn
1097-0258pii
10.1002/(SICI)1097-0258(19980815/30)17:15/16<1691:journal_volume
17pub_type
杂志文章abstract::Antimicrobial resistance has become one of the main public health burdens of the last decades, and monitoring the development and spread of non-wild-type isolates has therefore gained increased interest. Monitoring is performed based on the minimum inhibitory concentration (MIC) values, which are collected through the...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.5939
更新日期:2014-01-30 00:00:00
abstract::Statistical methods are available for performing a meta-analysis when the response variable of interest is the same in each study. Problems arise when studies exploring a common therapeutic question use different patient response types. This article presents statistical methods for combining studies which involve diff...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.4780132313
更新日期:1994-12-15 00:00:00
abstract::The generalized estimating equations (GEE) approach is commonly used to model incomplete longitudinal binary data. When drop-outs are missing at random through dependence on observed responses (MAR), GEE may give biased parameter estimates in the model for the marginal means. A weighted estimating equations approach g...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.1241
更新日期:2002-10-30 00:00:00
abstract::Biological drug products are therapeutic moieties manufactured by a living system or organisms. These are important life-saving drug products for patients with unmet medical needs. Because of expensive cost, only a few patients have access to life-saving biological products. Most of the early biological products will ...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.5565
更新日期:2013-02-10 00:00:00
abstract::To summarize safety data such as clinical adverse experiences in clinical trials with a moderate to long-term follow-up, we may use a measurement which accounts for the potential differences in the follow-up duration between treatment groups. The incidence rate, which uses the total person-time follow-up in a treatmen...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.2335
更新日期:2006-04-30 00:00:00
abstract::Genetic networks for gene expression data are often built by graphical models, which in turn are built from pair-wise correlations of gene expression levels. A key feature of building graphical models is the evaluation of conditional independence of two traits, given other traits. When conditional independence can be ...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.3274
更新日期:2008-08-30 00:00:00
abstract::A measure of similarity for response curves is presented and its potential use is discussed. The distribution of a suitable test statistic for testing the independence of the course of two curves is derived. The method proposed is compared with other proposals in the literature for the analysis of paired response curv...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.4780081112
更新日期:1989-11-01 00:00:00
abstract::We present an estimate of the kappa-coefficient of agreement between two methods of rating based on matched pairs of binary responses and show that the estimate depends on the common intraclass correlation coefficient between the pairs. Via Monte Carlo simulation, we investigate power of the test of significance on ka...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.4780140109
更新日期:1995-01-15 00:00:00
abstract::Prognostic models are used in medicine for investigating patient outcome in relation to patient and disease characteristics. Such models do not always work well in practice, so it is widely recommended that they need to be validated. The idea of validating a prognostic model is generally taken to mean establishing tha...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/(sici)1097-0258(20000229)19:4<453::aid-sim
更新日期:2000-02-29 00:00:00
abstract::A frequent objective in medical research is the investigation of differences in patient survival between several experimental treatments and one standard treatment. In order to assess these differences statistically, we have to apply adjustments for multiple comparisons to prevent an increased number of false-positive...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.4403
更新日期:2012-01-13 00:00:00
abstract::We propose a joint model for a time-to-event outcome and a quantile of a continuous response repeatedly measured over time. The quantile and survival processes are associated via shared latent and manifest variables. Our joint model provides a flexible approach to handle informative dropout in quantile regression. A M...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.6393
更新日期:2015-03-30 00:00:00
abstract::The publication of Fisher's correspondence on statistics has shed new light on his views on randomization. Quotations from this correspondence and from other works of Fisher are used to illustrate the role of randomization in clinical trials. It is concluded that Fisher's views not only are coherent but, despite havin...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.4780130305
更新日期:1994-02-15 00:00:00
abstract::We obtained maximum likelihood estimates (MLEs) of the proportion cured pi c and mean log survival time mu t for a sample of 4355 patients with intraocular melanoma whose survival times subsequent to treatment were assumed to follow a log-normal distribution. Following stratification by tumour size, MLEs of pi c and m...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.4780090814
更新日期:1990-08-01 00:00:00
abstract::In a typical bioequivalence trial, summary measures of the plasma concentration versus time profile are used to compare two formulations of a drug product. Commonly used measures include area under the curve (AUC), maximum plasma concentration (C(max)) and time to maximum concentration (T(max)). Equivalence of these s...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/1097-0258(20001030)19:20<2855::aid-sim550>
更新日期:2000-10-30 00:00:00
abstract::In this paper we examine the efficiency of a generalization of the traditional normal linear (LDA) or quadratic (QDA) discriminant analysis. This procedure (the generalized discriminant analysis, GDA) replaces each normal density used in the traditional classification rule by a Fourier series density estimator which '...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.4780100319
更新日期:1991-03-01 00:00:00
abstract::A mixture model incorporating long-term survivors has been adopted in the field of biostatistics where some individuals may never experience the failure event under study. The surviving fractions may be considered as cured. In most applications, the survival times are assumed to be independent. However, when the survi...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.932
更新日期:2001-06-15 00:00:00
abstract::Although statistical methodology is well-developed for comparing diagnostic tests in terms of their sensitivity and specificity, comparative inference about predictive values is not. In this paper, we consider the analysis of studies comparing operating characteristics of two diagnostic tests that are measured on all ...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.6485
更新日期:2015-07-10 00:00:00
abstract::In noninferiority studies, a limit of indifference is used to express a tolerance in results such that the clinician would regard such results as being acceptable or 'not worse'. We applied this concept to a measure of accuracy, the Receiver Operating Characteristic (ROC) curve, for a sequence of tests. We expressed a...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.5741
更新日期:2013-07-20 00:00:00
abstract::Various aspects of portfolio management and project prioritization within the pharmaceutical industry are examined. It is shown that the cost and probability architecture of a project is a crucial aspect of its value. An appropriate simple tool for ranking projects is the Pearson index. Various difficulties are consid...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/(SICI)1097-0258(19961230)15:24<2689::AID-S
更新日期:1996-12-30 00:00:00
abstract::We extend the method proposed in a recent work by the Authors for trial-level general surrogate evaluation to allow combinations of biomarkers and provide a procedure for finding the "best" combination of biomarkers based on the absolute prediction error summary of surrogate quality. We use a nonparametric Bayesian mo...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.7996
更新日期:2019-03-30 00:00:00
abstract::Recently, Wu and Follmann developed summary measures to adjust for informative drop-out in longitudinal studies where drop-out depends on the underlying true value of the response. In this paper we evaluate these procedures in the common situation where drop-out depends on the observed responses. We also discuss vario...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/1097-0258(20010115)20:1<93::aid-sim655>3.0
更新日期:2001-01-15 00:00:00
abstract::In US states with small subpopulations, the observed mortality rates are often zero, particularly among young ages. Because in life tables, death rates are reported mostly on a log scale, zero mortality rates are problematic. To overcome the observed zero death rates problem, appropriate probability models are used. U...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.6385
更新日期:2015-05-20 00:00:00
abstract::The risk that a drug newly introduced into medical use will occasionally cause adverse reactions is neither negligible nor totally avoidable. Only well organized systems of monitoring can bring early detection and appropriate action. These in turn require either detailed supervision or spontaneous reporting. The paper...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.4780010208
更新日期:1982-04-01 00:00:00
abstract::The intraclass correlation coefficient rho plays a key role in the design of cluster randomized trials. Estimates of rho obtained from previous cluster trials and used to inform sample size calculation in planned trials may be imprecise due to the typically small numbers of clusters in such studies. It may be useful t...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.1643
更新日期:2003-12-30 00:00:00
abstract::Conditional power (CP) is the probability that the final study result will be statistically significant, given the data observed thus far and a specific assumption about the pattern of the data to be observed in the remainder of the study, such as assuming the original design effect, or the effect estimated from the c...
journal_title:Statistics in medicine
pub_type: 杂志文章,评审
doi:10.1002/sim.2151
更新日期:2005-09-30 00:00:00
abstract::A technique is presented which provides guidance on the spacing of follow-up waves in a multiwave study. Only information from the baseline wave is needed, as well as rough parameter estimates for the survival distribution. The computations use the expected Fisher information; a new method for its calculation is given...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.4780101209
更新日期:1991-12-01 00:00:00
abstract::The design of a cross-sectional survey to estimate the age-specific incidence of an irreversible disease is considered, where the incidence rate is not changing over time and the risk of mortality is not affected by the onset of disease. The sample is assumed to give information on the current age and disease status o...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.4780132208
更新日期:1994-11-30 00:00:00
abstract::Algorithms for identifying public health threats or disease outbreaks are vulnerable to false alarms arising from sudden shifts in health-care utilization or data participation. This paper describes a method of reducing false alerts in automated public health surveillance algorithms, and in particular, automated syndr...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.4204
更新日期:2011-06-30 00:00:00
abstract::Most statistical methodology for phase III clinical trials focuses on the comparison of a single experimental treatment with a control. An increasing desire to reduce the time before regulatory approval of a new drug is sought has led to development of two-stage or sequential designs for trials that combine the defini...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.1362
更新日期:2003-03-15 00:00:00
abstract::We survey models for analysing repeated observations on an ordered categorical response variable. The models presented are univariate models that permit correlation among repeated measurements. The models describe simultaneously the dependence of marginal response distributions on values of explanatory variables and o...
journal_title:Statistics in medicine
pub_type: 杂志文章
doi:10.1002/sim.4780081005
更新日期:1989-10-01 00:00:00