• The Korean Journal of Applied Statistics
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• v.29 no.2
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• pp.279-289
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• 2016

Bioequivalence trials based on higher order crossover designs have recently been conducted for highly variable drugs since the Ministry of Korea Food and Drug Safety (MFDS) added new regulations in 2013 to widen bioequivalence limits for highly variable drugs. However, a statistical discussion of higher order crossover designs have not been discussed yet. This research proposes the statistical inference of bioequivalence based on $3{\times}3$ crossover design and discusses it with the MFDS regulations. An illustrated example is also given.

• The Korean Society of Law and Medicine
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• v.22 no.1
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• pp.91-124
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• 2021

In May 2019, the Ministry of Food and Drug Safety revised the "Pharmaceutical Determination and Adjustment Criteria" with the content of differentially calculating the price of generic drugs according to the registration of the drug substance and meeting the requirements for their own bioequivalence test. According to this revised rule, if their own bioequivalence test is not conducted, even the generic drugs that have already been approved would be lowered in price. I wondered whether this system was introduced with sufficient public legal considerations regarding its legislative purposes and means. Therefore, I reviewed the contents of the revised notice based on whether or not it is valid to determine and adjust the price of generic drugs in terms of the legitimacy of legislative purposes and the proportionality principle after introducing the history and background of the rule. First, I raised a question as to whether the purpose of preventing the overrun of generic drugs is indeed legitimate in terms of the legitimacy of the purpose. In order for the revised notice of "reduction of drug prices when the test requirements are not met," to meet the conformity principle, the premise that it is difficult to recognize safety and effectiveness through consignment (joint) bioequivalence test or that these tests are insufficient in safety and efficacy verification than their own test must be established. Nevertheless, it seems that suffficient review has not been carried out. In order to achieve the purpose of securing safety and effectiveness, the focus should be on 'reinforcement of the standards for bioequivalence test and the management of the bioequivalence test itself' rather than whether it is a their own test or a consignment (joint) test. Third, it is contrary to the necessity and substantiality principle that strict standards are uniformly applied to the products that can be considered to have been sufficiently verified for safety and effectiveness after a considerable period of time has passed after the product approval. In many cases, revised administrative legislations quickly enacted and amended in the state of lack of legal review or consensus, while the regulatory effects resulting from it are quite direct and specific to the regulated person. In this respect, I emphasized that the administrative legislative process also requires substantial review and prior control of the regulatory purposes and means, and that the participation of stakeholders in the legislative procedure is to be strengthened.

• Communications for Statistical Applications and Methods
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• v.16 no.5
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• pp.745-751
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• 2009

Outlying or extreme observations are defined to be subject data for which one or more bioavailability measures are discordant with corresponding data for that subject and/or for the rest of the subjects in a study. The presence of outlying observations can have very serious consequences on the conclusions resulting from a bioequivalence study. Two statistical methods are proposed by generalizing the current well known methods and an illustrated example is presented with discussion.

• The Korean Journal of Applied Statistics
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• v.28 no.2
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• pp.289-294
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• 2015

Linear mixed models are commonly used in the clinical pharmaceutical studies to analyze repeated measures such as the crossover study data of bioequivalence studies. In these models, random effects describe the correlation between repeated outcomes and variance-covariance matrix explain within-subject variabilities. Bioequivalence analysis verifies whether a 90% confidence interval for geometric mean ratio of Cmax and AUC between reference drug and test drug is included in the bioequivalence margin [0.8, 1.25] performed using linear mixed models with period, sequence and treatment effects as fixed and sequence nested subject effects as random. A Levofloxacin study is referred to for an example of real data analysis.

• Korean Journal of Breeding Science
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• v.40 no.3
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• pp.303-307
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• 2008

We bred a new green-kerneled glutinous rice variety that can be cultivated in the whole area of Korea, because only one native green-kerneled glutinous rice cultivar, "Saengdongchalbyeo", has been cultivated in the southern coastal area due to its late heading. The seeds of "Saengdongchalbyeo" were irradiated with 200 Gy of gamma ray in 1995. A promising mutant variety, "Nogwonchalbyeo" ("Wonnong 17") was selected through line selection and regional yield trials. In particular, the new variety revealed at the earlier mid of August compared to that of "Saengdongchalbyeo", the early of September, and it was considerably tolerant to a field lodging due to its shortened culm length. Also, "Nogwonchalbyeo" had a higher ripened grain ratio and 1,000 grain weight compared to the original variety. The brown grain yield of the new variety was about 5.40 MT/ha, which was 11.3% higher than that of the original variety, in the regional yield trials at 3 different fields during 2000~2001. The brown and milled grains of the new rice variety contained 20 to 65% higher amount of total amino acids, respectively than that of the original and two checks. For chlorophyll -a, -b and total chlorophyll, the new variety showed nearly two-fold higher than the checks, and for the carotenoid, it had 5.3 - 7.6 times higher amount. These results showed that the new variety can be cultivated as a special green-kerneled glutinous rice with high functional compounds.

• The Korean Journal of Applied Statistics
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• v.18 no.1
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• pp.159-171
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• 2005

The US Food and Drug Administration(FDA) recommends that population bioequivalence and individual bioequivalence would be assessed to address the prescribability and switchability between a brand-name drug and its new formulation or generic copy in its 2001 guidance document. The test for population bioequivalence in the latest FDA guidance is recommended in 2 x 4 crossover design, but it turns out to be very conservative. Recently Lee, Shao & Chow(2002), Chow, Shao & Wang(2003) and McNally, Iyer & Mathew(2002) proposed new statistical methods for assessing population bioequivalence between drugs to correct the biasness of current FDA method. Since 2 x 2 crossover experiment is most welcomed design in bioequivalence testing, we adopt their methods to 2 x 2 crossover designs and compare their methodologies with FDA one through the simulation study.

• Journal of the Korean Data and Information Science Society
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• v.28 no.4
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• pp.743-754
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• 2017

Assessing bioequivalence between original drug and generic drug is traditionally based on $2{\times}2$ crossover design. As bioequivalence trials for highly variable drugs are getting popular, the required sample size based on $2{\times}2$ crossover design would be very large, which might cause the ethical concerns. Regulatory agencies like EMA and MFDS recommended higher order crossover designs such as $2{\times}4$, $4{\times}2$ and $4{\times}4$ crossover designs. Alternatively, a $2{\times}3$ dual design may be recommended in terms of economical and ethical points of view in comparison with the $2{\times}4$ crossover design for highly variable drug. In this study, we consider some statistical characteristics of $2{\times}3$ dual design and propose statistical procedures for calculating sample size and assessing bioequivalence based on $2{\times}3$ dual design. We also discuss the proposed procedures from the perspective of newly revised bioequivalence guidance issued by MFDS.

• The Korean Journal of Applied Statistics
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• v.23 no.1
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• pp.139-150
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• 2010

In recent years, more generic drug products became available. The current regulation for assessing the bioequivalence of two drug formulations is based on the concept of average bioequivalence. This approach has been indicated to be insufficient for assessing switchability between two drug formulations and US FDA has adopted individual bioequivalence as one of the bioequivalence criterion since 2001. The US FDA recommends that individual bioequivalence be assessed based on $2\;{\times}\;4$ crossover design, while a $2\;{\times}\;3$ crossover design may be used as an alternative design to reduce the length and cost of the study. In this paper, a statistical procedure for assessment of individual bioequivalence under $3\;{\times}\;2$ crossover designs is proposed and some statistical points are discussed with $2\;{\times}\;3$ crossover design and $2\;{\times}\;3$ extra-reference design through simulation studies.

• Spatial Information Research
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• v.8 no.1
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• pp.51-67
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• 2000

This was preliminary research to develop the mapping method for the Urban Ecological Map. This research provided preliminary evaluation model for ecological conservation. The model was applied to Mt. Kwanak in Seoul, and the Urban Ecological Map was produced and tested. The results are as follows. First, some problems were found in the legal Ecological Map ; insufficient and only qualitative criteria for evaluation of the conservation value in an urban area, and exclusion of the areas designated by other was laws. Secondly, in order to improve the evaluation criteria for Ecological Map, some missed sites should be added to the legal list of valuable sites. Those are needed for ecological restoration, conservation of wildlife habitats managed by a city government , and establishment of eco-corridor. Third, the efficient mapping process for Urban Ecological Map must have two steps. On the first step an ecological evaluation should be done based on pure conservation value. On the second one the Ecological Map for legal action control should be made. And the Analytic Hierachy Process is considered as a Helpful technique for improving the objectivity of evaluation model. Fourth, the legal action control system for Urban Ecological Map should be reviewed.