Design and evaluation of multiregional trials with heterogeneous treatment effect across regions

To speed up drug development to allow faster access to medicines for patients globally, conducting multiregional trials incorporating subjects from many countries around the world under the same protocol may be desired. Several statistical methods have been proposed for the design and evaluation of multiregional trials. However, in most of the recent approaches for sample size determination in multiregional trials, a common treatment effect of the primary endpoint across regions is usually assumed. In practice, it might be expected that there is a difference in treatment effect due to regional difference (e.g., ethnic difference). In this article, a random effect model for heterogeneous treatment effect across regions is proposed for the design and evaluation of multiregional trials. We also address consideration of the determination of the number of subjects in a specific region to establish the consistency of treatment effects between the specific region and the entire group.     

Statistical design of noninferiority multiple region clinical trials to assess global and consistent treatment effects

Noninferiority multiregional clinical trials (MRCTs) have recently received increasing attention in drug development. While a major goal in an MRCT is to estimate the global treatment effect, it is also important to assess the consistency of treatment effects across multiple regions. In this paper, we propose an intuitive definition of consistency of noninferior treatment effects across regions under the random-effects modeling framework. Specifically, we quantify the consistency of treatment effects by the percentage of regions that meet a predefined treatment margin. This new approach enables us to achieve both goals in one modeling framework. We propose to use a signed likelihood ratio test for testing the global treatment effect and the consistency of noninferior treatment effects. In addition, we provide guidelines for the allocation rule to achieve optimal power for testing consistency among multiple regions. Extensive simulation studies are conducted to examine the performance of the proposed methodology. An application to a real data example is provided.     

On evaluation of consistency in multi-regional clinical trials

In recent years, multi-regional clinical trials (MRCT) that conduct clinical trials simultaneously in Asian Pacific region, Europe, and the United States have become very popular for global pharmaceutical development. The main purpose of multi-regional clinical trials is to shorten the time for pharmaceutical development and regulatory submission, and approval around the world. In practice, however, clinical results observed from some regions (sub-population) may not be consistent with the results from other regions and/or all regions combined (entire population). The inconsistency observed may be due to ethnic differences in different regions, differences in medical practice, time points of assessment, or by random chance due to small sample size for the region. Some regional regulatory agencies require consistency evaluation between local country results and overall results. However, the challenge is there is no detailed guidance on the definition of ‘consistency’ and methodology to evaluate it. Therefore, the questions are: how to evaluate consistency and what statistical methods are appropriate to be used for consistency evaluation? In this article, several statistical tests for consistency (similarity) between clinical results observed from a specific sub-population and the entire population are proposed. These methods are compared through extensive simulation. As most published articles discussed consistency evaluation for superiority situations, we have discussed consistency evaluation for non-inferiority situation in this article through a simulated example concerning consistency in some countries. Recommendations of the statistical methods to be used for consistency evaluation are given. Other aspects that should be considered for consistency evaluation are also provided.     

Sample Size Determination for a Specific Region in a Multiregional Trial

Recently, geotherapeutics have attracted much attention from sponsors as well as regulatory authorities. A bridging study defined by the International Conference on Harmonisation (ICH) E5 is usually conducted in the new region after the test product has been approved for commercial marketing in the original region due to its proven efficacy and safety. However, extensive duplication of clinical evaluation in the new region not only requires valuable development resources but also delays availability of the test product to the needed patients in the new regions. To shorten the drug lag or the time lag for approval, simultaneous drug development, submission, and approval in the world may be desirable. On September 28, 2007, the Ministry of Health, Labour and Welfare (MHLW) in Japan published the “Basic Principles on Global Clinical Trials” guidance related to the planning and implementation of global clinical studies. The 11th question and answer for the ICH E5 guideline also discuss the concept of a multiregional trial. Both guidelines have established a framework on how to demonstrate the efficacy of a drug in all participating regions while also evaluating the possibility of applying the overall trial results to each region by conducting a multiregional trial. In this paper, we focus on a specific region and establish statistical criteria for consistency between the region of interest and overall results. More specifically, four criteria are considered. Two criteria are to assess whether the treatment effect in the region of interest is as large as that of the other regions or of the regions overall, while the other two criteria are to assess the consistency of the treatment effect of the specific region with other regions or the regions overall. Sample size required for the region of interest can also be evaluated based on these four criteria.     

多中心临床试验疗效一致性评价方法

随着临床试验全球化的增长趋势,多中心临床试验已经受到了广泛的关注。其中各个中心治疗效果的一致性评价是多中心临床试验中的一个关键问题。本文系统综述了关于多中心临床试验在评价整体一致性中的常用方法,对一致性评价方法的选择、检验的功效和假阳性的概率以及样本容量与方法之间的关系给出了一些简单的讨论,旨在为从事多中心临床工作者提供借鉴,希望有更多的国内学者关注这一领域的研究,推动多中心临床试验在我国的发展,为新药临床试验提供理论依据。     

Assessment of regional treatment effect in a multiregional clinical trial

The 11th question-and-answer document (Q&A) for ICH E5 ( 1998 ) was published in 2006. This Q&A describes points to consider for evaluating the possibility of bridging among regions by a multiregional trial. The primary objective of a multiregional bridging trial is to show the overall efficacy of a drug in all participating regions while also evaluating the possibility of applying the overall trial results to each region. To apply the overall results to a specific region, it suggested that the results in that region should be consistent with the overall results. The Japanese Ministry of Health, Labor, and Welfare (MHLW) published the "Basic Principles on Global Clinical Trials" guidance document (2007) and proposed two methods to support the bridging claims. Due to the limited sample sizes allocated to the region, the regular interaction test for treatment by region is not practical. On the other hand, the sample size requirement for the Japanese region as described in Uyama et al. ( 2005 ) and Uesaka ( 2009 ) is to satisfy an 80% or greater power for the Japanese region, conditioning on the effect of the overall global trial. Quan et al. ( 2010 ) further extended the results to trials with various endpoints. Ko, Tsou, Liu and Hsiao ( 2010 ) focused on a specific region and established statistical criteria for consistency between the region of interest and overall results. The proposed method was based on the assumption that true effect size is uniform across regions. In this article, we propose to analyze a completed multiregional trial for any specific regional effect by controlling the type I error rate adjusted for the regional sample size and the planned power of the global trial. Accordingly, in order to attain the approval for a specific region, we propose to determine the sample size requirement for the specific regions using the overall power planned and a regional acceptable type I error rate.     

Practical Recommendations for Regional Consistency Evaluation in Multi-Regional Clinical Trials with Different Endpoints

In recent years, there is an increasing trend to conduct multi-regional clinical trials (MRCT) for drug development in pharmaceutical industry. A carefully designed MRCT could be used in supporting the new drug's approval in different regions simultaneously. The primary objective of an MRCT is to investigate the drug's overall efficacy across regions while also assessing the drug's performance in some specific regions. In order to claim the study drug's efficacy and get drug approval in some specific region(s), the local regulatory authority may require the sponsors to provide evidence of consistency in the treatment effect between the overall patient population and the local region. Usually, the regional specific consistency requirement needs to be pre-specified before the study conduct and the consistency in treatment effect between the region(s) of interest and overall population will be evaluated at the final analysis. In this article, we evaluate the consistency requirements in multi-regional clinical trials for different endpoints, that is, continuous, binary, and survival endpoints. We also compare the different consistency requirements of the same endpoint/measurement if multiple consistency requirements are enforced and our recommendations for each endpoint/measurement will be made based on the comprehensive consideration.     

A nested group sequential framework for regional evaluation in global drug development program

The primary objective of a multiregional clinical trial (MRCT) is to assess the efficacy of all participating regions and evaluate the probability of applying the overall results to a specific region. The consistency assessment of the target region with the overall results is the most common way of evaluating the efficacy in a specific region. Recently, Huang et al. (2012) proposed an additional trial in the target region to an MRCT to evaluate the efficacy in the target ethnic (TE) population under the framework of simultaneous global drug development program (SGDDP). However, the operating characteristics of this statistical framework were not well considered. Therefore, a nested group sequential program for regional efficacy evaluation is proposed in this paper. It is an extension of Huang’s SGDDP framework and allows interim analysis after MRCT and in the course of local clinical trial (LCT) phase. It is able to well control the family-wise type I error in the program level and enhances the flexibility of the program. In LCT sample size estimation, we introduce virtual trial, which is transformed from the original program by using discounting factor, and an iteration method is employed to calculate the sample size and stopping boundaries of interim analyses. The proposed sample size estimation method is validated in the simulations and the effect of varied weight, effect size of TE population, and design setting is explored. Examples with normal end point, binary end point, and survival end point are shown to illustrate the application of the proposed nested group sequential program.     

Sample Size Allocation to Regions in a Multiregional Trial

The objective of a multiregional bridging trial is to show the efficacy of a drug in various global regions, and at the same time to evaluate the possibility of applying the overall trial results to each region. However, to apply overall results to a specific region, the result in that region should be consistent with either the overall results or the results of other regions. This article discusses methods of sample size allocation to regions by introducing statistical criteria for consistency between regional and overall results. Specifically, three rules of sample size allocation are discussed: (1) allocating equal size to all regions, (2) minimizing total sample size, and (3) minimizing the sample size of a specific region. Some total and regional sample sizes calculated under each allocation rule are illustrated.     

Qualitative consistency of treatment effects in multiregional clinical trials

Consistency of treatment effects across different regions in multiregional clinical trials (MRCTs) has been an important question for the regulatory authorities. Many consistency definitions are proposed in literature. One of the definitions of consistency is expressed as qualitative consistency, whereas inconsistency is defined as qualitative treatment by region interaction. This article focuses on the qualitative consistency and extends Gail-Simon and Sasabuchi's one-sided multivariate likelihood ratio tests. Simulations are used to evaluate operating characteristics of these qualitative consistency assessment approaches. For a given number of regions, the guideline for setting significance level, and consistency cut-off are explored.     

Unified additional requirement in consideration of regional approval for multiregional clinical trials

To speed up the process of bringing a new drug to the market, more and more clinical trials are being conducted simultaneously in multiple regions. After demonstrating the overall drug’s efficacy across regions, the regulatory and drug sponsor may also want to assess the drug’s effect in specific region(s). Most of the recent approaches imposed a uniform criterion to assess the consistency of treatment effects between the interested region(s) and the entire study population regardless of the number of regions in multiregional clinical trials (MRCT). As a result, the needed sample size to achieve the desired probability of satisfying the regional requirement could be huge and implausible for the trial sponsors to implement.

In this paper, we propose a unified additional requirement for regional approval by differing the parameters in the additional requirement depending on the number of planned regions. In particular, the values of the parameters are determined by a reasonable sample size increase with the desired probability satisfying the additional requirement. Considering the practicality of the global trial or sample size increase, we recommend specific values of the parameters for a different number of planned regions. We also introduce the assurance probability curve to evaluate the performance of different regional requirements.     

The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys.

It is unclear to what degree antipsychotic therapy confounds longitudinal imaging studies and post-mortem studies of subjects with schizophrenia. To investigate this problem, we developed a non-human primate model of chronic antipsychotic exposure. Three groups of six macaque monkeys each were exposed to oral haloperidol, olanzapine or sham for a 17-27 month period. The resulting plasma drug levels were comparable to those seen in subjects with schizophrenia treated with these medications. After the exposure, we observed an 8-11% reduction in mean fresh brain weights as well as left cerebrum fresh weights and volumes in both drug-treated groups compared to sham animals. The differences were observed across all major brain regions (frontal, parietal, temporal, occipital, and cerebellum), but appeared most robust in the frontal and parietal regions. Stereological analysis of the parietal region using Cavalieri's principle revealed similar volume reductions in both gray and white matter. In addition, we assessed the subsequent tissue shrinkage due to standard histological processing and found no evidence of differential shrinkage due to drug exposure. However, we observed a pronounced general shrinkage effect of approximately 20% and a highly significant variation in shrinkage across brain regions. In conclusion, chronic exposure of non-human primates to antipsychotics was associated with reduced brain volume. Antipsychotic medication may confound post-mortem studies and longitudinal imaging studies of subjects with schizophrenia that depend upon volumetric measures.     

Pharmacokinetics of Orally Inhaled Drug Products

The presentations at the Orlando Inhalation Conference on pharmacokinetic (PK) studies indicated that PK is the most sensitive methodology for detecting formulation differences of oral inhaled drug products (OIDPs) that have negligible gastrointestinal bioavailability or for which oral absorption can be prevented (e.g., ingestion of charcoal). PK studies, therefore, may represent the most appropriate methodology for assessing local and systemic bioequivalence (BE). It was believed by many (but not all participants) that potential differences between formulations are more likely to be detected in healthy adult volunteers, as variability is reduced while deposition to peripheral areas is not restricted. A study design allowing assessment and statistical consideration of intra-subject and inter-batch variability within the evaluation of BE studies was suggested, while optimal inhalation technique during PK studies should be enforced to decrease variability. Depending on the drug and in vitro method, in vitro tests may not detect differences in PK parameters. Harmonization of BE testing requirements among different countries should be encouraged to improve global availability of low cost OIDPs and decrease industry burden.     

Within- and between-subject variability in the reinforcing and subjective effects of nitrous oxide in healthy volunteers

Within- and between-subject variability in the reinforcing and subjective effects of nitrous oxide (N(2)O) was studied across five sessions. Twelve volunteers with no history of drug dependence sampled 30% N(2)O and 100% oxygen for 10 min each, then chose nine times, once every 5 min, among N(2)O (e.g. "Agent A"), oxygen (e.g. "Agent B"), or "drug-free air." Choice varied across subjects but was stable within subjects. Quantitative differences in subjective effects occurred within and across subjects. Some subjective effects were correlated with choice and/or differed between subjects who were consistent choosers of N(2)O versus those who were not. However, drug liking and euphoria, two face-valid measures of abuse liability, were unrelated to choice. Thus, the present study found individual differences (i.e. between-subject variability) in subjective and reinforcing effects of N(2)O and, in terms of within-subject variability, suggested that subjective effects fluctuate across sessions to a relatively greater extent than do reinforcing effects. The varying degrees of correlation between N(2)O choice and its subjective effects emphasize the need for obtaining multiple measures when characterizing abuse liability of this drug.     

浅谈药物流行病学和药品评价的发展与国际现状

药物流行病学是把流行病学的方法、知识和推理应用到临床药理学中,并以此为基础对特定人群或特定药品的使用情况、有效性及安全性进行集中研究,在对药品进行研究和评价的过程中起着十分重要的作用.同时,药物流行病学与药品评价的应用研究已经贯穿于药品的整个研发、使用、甚至流通等诸多领域,直接为制定相关治疗指导原则、国家药品政策提供依据.本文从药物流行病学的历史和发展、药物流行病学常用的研究方法、药物流行病学和药品评价在药品审批和管理过程中的应用以及非政府组织对药物流行病学和药品评价研究的推动等方面入手,着重分析了药物流行病学和药品评价的国际现状.     

A Bayesian Approach to Evaluating Regional Treatment Effect in a Multiregional Trial

A multiregional trial, conducted in more than one region under a common protocol, is a promising strategy making valuable medicines available to patients globally without time lag. When evaluating the treatment effect for each local region, one may wish to utilize information from other regions to enhance the statistical power. This work proposes a Bayesian approach to bridging data across different regions in a multiregional trial to get an improved analysis of treatment effect for a local region. The new proposal has the following distinct features: (1) It performs internal bridging in a multiregional trial, with the degree of bridging automatically determined by the interregional variability of the treatment effect across different regions; (2) it usually ensures the consistency of the conclusions from local and global inference when the treatment effect is virtually homogeneous across regions and is found nonsignificant globally; (3) it generally protects against overbridging of the global information for evaluating the treatment effect in a very small region. Formulas for statistical power of the proposed method are provided. We illustrate the utility of the proposed method by two numerical examples reflecting typical issues we may encounter in evaluating regional treatment effect in a multiregional trial.     

Matching strategies for drug studies of prepulse inhibition in humans

Prepulse inhibition (PPI), a measure of sensorimotor gating, is impaired in certain neuropsychiatric disorders. Animal studies have revealed drug effects on PPI that may be relevant to understanding the biology of gating deficits in human populations. Recent efforts have examined similarities and differences in drug effects on PPI between rodents and humans. Experimental designs are needed that most effectively translate these drug studies across species. In the course of a larger set of studies of drug effects on startle in normal human subjects, we examined the potential utility of one design element that is utilized in rodent PPI drug studies: pre-testing to diminish variability across dose groups. Startle was measured during a screening session; 7-10 days later, 20 subjects were retested after consuming a placebo pill. Acoustic and tactile startle, and unimodal and cross-modal PPI, were measured in five sessions over a period of 3 hours post-placebo. There were significant and robust correlations between levels of startle magnitude and PPI during pre-testing and testing, for both left and right eyeblink measures. Comparable correlations were evident for both unimodal and cross-modal testing. Pre-testing values were most predictive of test performance early in the 3-hour test session, and predictive strength diminished or disappeared towards the end of testing. The utility of a pre-testing design could be seen clearly by comparing groups 'matched', based on pre-test data, versus groups created by alternating or random group assignments. It is concluded that pre-test designs can effectively match groups with comparable levels of startle or PPI, and thereby diminish between-group variability in human PPI drug studies. For studies using repeated testing to assess drug time course, the predictive value of pre-testing is greatest in early test sessions.     

A comparative assessment of amlodipine and felodipine ER: pharmacokinetic and pharmacodynamic indices

Summary This study investigated potential therapeutic differences between Amlodipine 5 mg and Felodipine ER 10 mg in 12 normotensive/borderline hypertensive subjects by comparison of the plasma drug concentration-time profiles and the blood pressure and heart rate responses.There was significantly less trough-to-peak variability in plasma drug concentrations with amlodipine with a ratio of 67%, compared to 37% for felodipine. Correspondingly there was less variability with amlodipine in the blood pressure reductions across the dosage interval. Overall, amlodipine displayed a more consistent hypotensive effect across 24 hours and lower blood pressure values at trough, i. e. 24 hours post-dose.     

The interface between pharmacoepidemiology and pharmacogenetics

One of the most challenging areas of research in pharmacoepidemiology is to understand why individuals respond differently to drug therapy, both in terms of beneficial and adverse effects. Pharmacogenetics focuses on the question to what extent variability in genetic make-up is responsible for these observed differences. Pharmacoepidemiologic research can contribute to pharmacogenetics by explaining the observed variability in drug response in ‘real life’ patient populations with known polymorphisms in their genetic profile. Genetic pharmacoepidemiologists also are interested in the distribution of polymorphisms and correlated frequencies of responders and non-responders in the general population, and in searching for unknown genetic links to variability in drug response. In the future, we will probably have fewer drugs that suit all individuals. Genetic pharmacoepidemiology is going to play a major role in the development and evaluation of the concept of ‘tailor-made’ pharmacotherapy.     

Factors influencing the reinforcing and subjective effects of d-amphetamine in humans

The reinforcing and subjective effects of oral d-amphetamine (AMP) were studied in a group of non-drug abusing adults (16 males, 13 females). A discrete-trial choice procedure was used to assess the reinforcing effects of a single dose of AMP (range 7.5-20mg across subjects). A number of factors (gender, current and past drug use, personality, motor activity, and baseline mood state and psychophysiological and sensory indices of arousal) were examined in an attempt to explain both within- and between-subject variability in response to AMP. Of the 29 subjects, 11 chose AMP on either two or three out of a possible three occasions. Cigarette smokers reported stronger aversive responses to AMP and chose the drug significantly less often than non-smokers. Subjects with a history of non-medical stimulant use reported less subjective response to AMP than subjects without such history. Within-subject variability in AMP choice was related to variability in subjective response to the drug across choice trials, as well as to variability in baseline mood: AMP was more likely to be chosen when subjects were more aroused and in a more positive mood at the time of the choice. These results provide new information regarding factors that may be relevant in determining individual differences in vulnerability to abuse of psychomotor stimulants.