• 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.

• Korean Journal of Clinical Pharmacy
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• v.19 no.1
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• pp.50-60
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• 2009

Highly variable drugs (within-subject variability greater than 30%) have been difficult to meet current regulatory acceptance criteria using a reasonable number of study subjects. In this study, we reviewed previous studies presenting alternative approaches for bioequivalence evaluation of highly variable drugs, and focused on an approach for widening the bioequivalence acceptance limits using within-subject variability. We discussed the suggested five solutions for highly variable drug including the deletion of $C_{max}$ of the bioequivalence criteria, direct expansion of bioequivalence limit, multiple dose studies in steady state, bioequivalence assessment on the metabolite, add-on study, and widening the bioequivalence acceptance limits based on reference variability. The methods for widening of bioequivalence limits based on reference variability are scaled average bioequivalence containing within-subject variability on reference drug (${\sigma}_{WR}$), population bioequivalence derived from total variability on reference drug (${\sigma}_{TR}$) and test drug (${\sigma}_{TT}$), and individual bioequivalence derived from subject by formulation interaction variability (${\sigma}_D$) and within subject variability on reference drug (${\sigma}_{WR}$) and test drug (${\sigma}_{TR}$). To apply these methods, the switching variability (${\sigma}_0$) will have to be set by the regulatory authorities. The proposals of bioequivalence evaluation approach for the highly variable in Korea are presented for both of new drug and reevaluation drug.

• The Korean Journal of Applied Statistics
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• v.24 no.6
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• pp.1055-1076
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• 2011

This paper reviews the definition of highly variable drug(HVD), the present regulatory recommendations and the approaches proposed in the literature to deal with the bioequivalence issues of HVD. The concept and the statistical approach of scaled average bioequivalence(SABE) is introduced and discussed with the current regulatory methods. The recommendations for SABE approach are proposed and the further study topics related to HVDs are also presented.

• The Korean Journal of Applied Statistics
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• v.26 no.4
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• pp.675-686
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• 2013

The Korea Food and Drug Administration(KFDA) recommends the use of a $2{\times}2$ crossover design to assess the bioequivalence of generic drugs. However, a standard $2{\times}2$ crossover design for bioequivalence trials is often considered problematic due to ethical and economic issues as highly variable drugs are usually required by large numbers of subjects when designing the trial. To overcome this problem a $2{\times}4$ crossover design has been a recommended option as per US regulations; in addition, a $2{\times}3$ crossover design has also recently drawn special attention as an efficient alternative. The current KFDA regulation requires an ANOVA table for every bioequivalence study; however, ANOVA tables of $2{\times}4$ and $2{\times}3$ crossover designs have never been published in the literature. This study shows the derivation of tables of analysis of variance for a $2{\times}4$ cross-over design and a $2{\times}3$ cross-over design. We also suggest a sample size formulas for $2{\times}2$, $2{\times}4$ and $2{\times}3$ crossover designs to provide information on the selection of efficient designs for highly variable drugs.

• Journal of the Korean Data and Information Science Society
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• v.25 no.6
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• pp.1181-1193
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• 2014

Currently Ministry of food and drug safety allows add-on trial when the bioequivalence between two drugs fails to show since July 1, 2008. However, bioequivalence of highly variable drugs based on $2{\times}2$ crossover designs would require too many subjects, so the alternative designs like $2{\times}4$ or $2{\times}3$ crossover experiments are preferred. In this paper, we propose and discuss the statistical procedures for add-on trials in $2{\times}4$ and $2{\times}3$ crossover designs.

• 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.

• Korean Journal of Psychosomatic Medicine
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• v.7 no.2
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• pp.274-280
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• 1999

A variety of mechanism may generate pain resulting from injury to the central and peripheral nervous system. None of these mechanism is disease-specific, and several different pain mechanism may be simultaneously present in anyone patient, independent of diagnosis. Diagnosis of neuropathic pain is often easily made from information gathered on neurologic examination and from patient history. Although treatment of neuropathic pain may be difficult, optimum treatment can be achieved if the neurologist has a complete understanding of therapeutic options, the mainstay of which is pharmacotherapy. Selection of an appropriate rharmacologic agent is by trial and error since individual responses to different agents, doses, and serum levels are highly variable. An adequate trial for each agent tried is key to pharmacologic treatment of neuropathic pain. Tricyclic antidepressants are first-line agents, although other drugs, including anticonvulsants, local anesthetic antiarrhythmics, clonidine, opiates, and certain topical agents, also offer pain relief in some patient populations. The novel antidepressants venlafaxine and nefazodone are potentially useful new drugs that are better tolerated than tricyclic antidepressants. Also Gabapentine seems an interesting and promising drug for the treatment of neuropathic pain.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.272-272
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• 1996

While ranitidine is well known to be absorbed rapidly, the underlying cause of variable bioavailability in intra- and inter-subjects has not been clarified yet. Intestinal permeability is a key controlling factor for oral absorption of highly soluble drugs, In the present study, intestinal ferfusions have been conducted to determine the intestinal permeabilities(Peffs) of ranitidine in the rats, dogs and humans and compared to the estimated fractions of dose absorbed (FAs) in humans. A new in vivo methodology, using a regional segmental perfusion technique, has been used in the dogs and humans. In situ single-pass perfusion experiments have been performed in the rats. In the dog and human studies, perfusion experiments have been conducted on two periods to determine the intrasubject variability, There was low significant intrasubject variation as compared to intersubject variation. The Peffs of ranitidine were 33%, 51%, and 45% inthe rats, dogs and humans, respectively. The FAs were approximately the same for all three species models, suggesting rats and dogs are good animal models for estimating the oral absorption of ranitidine in humans. In addition, the estimated extent of absorption of this drug is consistent with the average bioavailability, indicating that ranitidine has permeability-limited absorption characteristics. Supported by FDA Grant FD01462.

• YAKHAK HOEJI
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• v.58 no.4
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• pp.229-244
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• 2014

Background: Antibiotic skin test(AST) is very useful for the diagnosis of drug allergies to prevent immediate allergic reactions. Although it is a safe and widespread method, it is performed very diversely by doctors and nurses without consistency and it also differs from countries and hospitals. This study aims to evaluate the current practice of AST by nurses in Korea and to compare it to the general guidelines. Methods: During January 1, 2013 to May 20, 2013, the study was conducted as questionnaires and case-based survey. The questionnaires were given to the nurses who were randomly selected in various University Hospitals (University Hospitals N=276, and Medical center N=19). The case-based surveys were given to the nurses who were conducting AST at various wards of a University Hospital (N=130). The analysis and evaluations of the responses were carried out. Results: The response rate for the questionnaires was 97.6% and 130 cases of the actual case-based surveys were collected. There were clear differences between the survey results and the general guidelines, such as the method of skin test (skin prick test was not conducted), the method of patient selection for AST, test drugs, concentration, volume and interpretation of AST. AST conducted by nurses was highly variable and inconsistent, even among nurses who worked in the same wards and hospitals. Manufactured standard concentration antibiotic solution of AST showed consistency of concentration to a certain degree. Conclusion: Although the general guidelines have been published by several countries including Korea, these are not a great help to nurses as they lack details for conducting AST, practical consideration for nurses in the clinical setting, propagation and education. Standardized guideline for nurses should be published and it should be a safe, clear, comfortable and easily accessible protocol. Futhermore, additional antibiotic solutions to standardize skin test should be developed and manufactured. Lastly, it would be the pharmacists role to compare their hospitals antibiotic skin test methods with the standard guidelines and develop a protocol within the hospital for patients' safety, and to strive to consistently implement it.