A group sequential approach to evaluation of bridging studies.
ABSTRACT The International Conference on Harmonization (ICH) E5 guideline defines a bridging study as a supplementary study conducted in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage, and dose regimen to allow extrapolation of the foreign clinical data to the population of the new region. Therefore, a bridging study is usually conducted in the new region only after the test product has been approved for commercial marketing in the original region due to its proven efficacy and safety. The issue of analysis of clinical data generated by the bridging study conducted in the new region to evaluate the similarity for extrapolation of the foreign clinical data to the population of the new region is the information on efficacy, safety, dosage, and dose regimen of the original region that cannot be concurrently obtained from the local bridging studies but is available in the trials conducted in the original region. A group sequential approach is therefore proposed to overcome the issue of internal validity. In particular, we use the region as a group sequence to enroll the patients from the original region first and then to enroll patients from the new region subsequently. Methods for sample size determination for the bridging study in the new region are also proposed.
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ABSTRACT: The world has become more interdependent in the movement of free trade and global markets. The regulations for approval of new drugs in the Asian markets have always been an important issue in the free trade negotiation between the U.S.- and E.U.-based international manufacturers and the Asian-Pacific countries, since pharmaceuticals are of large trade value for them. In 1998 the University of Hong Kong and the Singapore National Medical Research Council jointly hosted the first Asian Clinical Trials Conference. The Society for Clinical Trials was invited as a collaborator for the event, which signified a milestone for interaction between the East and West in the discussion of clinical trials. Many have participated in the discussion of drug approval and registration issues for the Asian region based on the drug development experience in the United States. However, there are many interesting differences between the two regions, which lead to different approval processes for new drugs developed by the U.S.- and E.U.-based international manufacturers. This article highlights some regulatory dilemmas and some key statistical concepts pertinent to these differences. The purpose of this paper is to resolve the regional regulatory and scientific dilemma. A new paradigm of sample size design and data analysis for drug approval for countries in the Asian-Pacific region is proposed. The central premise is that substantial information from multicenter studies has already shown efficacy in the United States or the European Union when a drug manufacturer seeks marketing approval in an Asian country. This leads to the idea of a "consistency trial" using the method of Bayesian most plausible prediction. The method is illustrated with an example.Controlled Clinical Trials 09/2001; 22(4):357-66.
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ABSTRACT: This paper proposes a nonparametric method for estimating a delay distribution based on left-censored and right-truncated data. A variance-covariance estimator is provided. The method is applied to the Australian AIDS data in which some data are left censored and some data are not left censored. This situation arises with AIDS case-reporting data in Australia because reporting delays were recorded only from November 1990 rather than from the beginning of the epidemic there. It is shown that inclusion of the left-censored data, as opposed to analyzing only the uncensored data, improves the precision of the estimate.Biometrics 07/1999; 55(2):345-9. · 1.41 Impact Factor
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ABSTRACT: In pharmaceutical industry, the sponsors are interested in bringing their drug products from one region (e.g., the United States of America) to another region (e.g., Asian Pacific) to increase the exclusivity of the drug products in the marketplace. However, it is a concern whether the clinical results can be extrapolated from the target patient population in one region to a similar but different patient population in a new region due to a possible difference in ethnic factors. The International Conference on Harmonization (ICH) recommends that a bridging study may be necessarily conducted to extrapolate the clinical results between regions. However, little or no information regarding the criterion for determining whether a bridging study is necessary based on the evaluation of the complete clinical data package is provided by the ICH. Furthermore, no criterion on the assessment of similarity of clinical results between regions is given. In this paper, we propose the use of a sensitivity index as a possible criterion for regulatory authorities in the new region to evaluate whether a bridging clinical study should be conducted and the sample size of such a bridging clinical study. A criterion and a statistical method for assessment of similarity of clinical results between regions are also proposed, using the concept of population bioequivalence [FDA. Guidance for Industry--Statistical Approaches to Establishing Bioequivalence, Center for Drug Evaluation and Research, Food and Drug Administration: Rockville, MD, 2001] assuming that study site is random.Journal of Biopharmaceutical Statistics 09/2002; 12(3):385-400. · 0.73 Impact Factor