JKSCPT Journal of Korean Society for Clinical Pharmacology and Therapeutics J Korean Soc Clin Pharmacol Ther 1225-5467 Korean Society for Clinical Pharmacology and Therapeutics 10.12793/jkscpt.2013.21.1.17 jkscpt-21-17 Original Article Establishment and Significance of Bioequivalence Recommendations for Individual Products-Drugs Acting on Circulatory System and Others BaeSoo Hyeon 1 ZhengYu Fen 2 KwonMin Jo 1 ChoiEu Jin 1 BaeSoo Kyung 1 College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-Do, Republic of Korea Department of Clinical Pharmacy, College of Pharmacy, Seoul National University, Seoul, Republic of Korea E-mail: baesk@catholic.ac.kr 01 2013 11 01 2013 211 17 25 23052013 24062013 25062013 Copyright © 2013 Korean Society for Clinical Pharmacology and Therapeutics 2013 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract

Along with the enactment of a law separating the prescribing and dispensing of drugs in Korea in 2000, attempts at reducing medical expenses by generic substitution have been allowed since August 2001 so long as generic products are bioequivalent to the original products. In the pharmaceutical industry, the required development and investment to make generic products are much less in terms of time and money. Thus, the number of bioequivalence studies in Korea has increased. This has resulted in the need for bioequivalence recommendations (guidelines), taking into account the circumstances of the Korean pharmaceutical industry. In this paper, we provide procedures for making bioequivalence determinations for individual products acting on the circulatory system (30 drugs, 2011), the components of which are widely accepted for the development of generic products in Korea. These recommendations correspond with international guidelines, such as those of the US FDA and EMEA. For the 30 drugs that act on the circulatory system, we examined each in terms of subject selection (healthy volunteers vs. patients), dosage strength, dosage route, analytes to measure, and evaluation parameters, and prepared bioequivalence recommendations for individual products through an analysis of many published papers, US FDA and EMEA guidelines, and clinical trial websites. Based on the bioequivalence recommendations for individual products, we had several meetings in which KFDA officers (members of the New Drug Research team and the Office of Generic Drugs), three pharmacy professors with expertise in drug analysis and pharmacokinetics, and three professors of medicine with extensive experience in clinical trials participated to confirm and discuss the contents. Finally, the bioequivalence recommendations for individual products were provided on the KFDA website. The individual bioequivalence recommendations have been used by KFDA officers in drug evaluations and bioequivalency testing to improve consistency, clarity, and professionalism in the drug evaluation process. These recommendations will be useful for domestic pharmaceutical companies by shortening the time and cost associated with bioequivalence studies, especially in terms of standardized trial designs, dosage forms, and analytical methods.

 Bioequivalence Recommendations (guidelines) Generic drugs REFERENCES Drug Approval ReportKFDA2011(Korean) KFDA Guideline for the Validation of Bioanalytical Methodhttp://drug.kfda.go.kr[Online] (last visited on 28 May 2013). Guidance for industry: Bioequivalence recommendations for specific productsUS FDA2010http://www.fda.gov/Drugs/GuidanceCompliance Regulatorylnformation/Guidances/default.htm[Online] (last visited on 28 May 2013). European public assessment reportsEMEAhttp://www.ema.europa.eu/ema[Online] (last visited on 28 May 2013). www.clinicaltrials.gov[Online] (last visited on 28 May 2013). Guideline for the Drug Equivalence Test(Notification No. 2001-71 of the KFDA, 2011. 11. 23). (Korean) KFDA Online drug libraryhttp://drug.kfckgo.kr[Online] (last visited on 28 May 2013). Figures and Tables

The number of bioequivalence tests approved in Korea (Drug Approval Report, KFDA, 2011).1)

Draft guidance on cilostazol (example).

Criteria for selection of 30 active ingredients

30 Active ingredients We finally choose 10 new drugs that have never been approved as generic drugs. However, two drugs were pharmaceutical equivalent,a,6) in terms of dissolution profiles(fluvastatin sodium and ezetimibe). We choose 4 drugs (active ingredients) which were not posted on the US FDA guidance.3)
We choose 6 active ingredients which were posted on the US FDA guidance.3)
Twenty drugs were pharmaceutical equivalent products in terms of dissolution profiles that were approved as genetic drugs. Of these, 12 drugs were both pharmaceutical equivalent products and new drugs. We choose 10 active ingredients which were not posted on the US FDA guidance.3)
We choose 10 active ingredients based on the data, top 10 lists, for financial burden of drug bills on 2011 from Korean Health Insurance Review & Assessment Service although they were posted on the US FDA guidance.3)

a) Drug equivalence test.

List of 30 active ingredients for bioequivalence recommendations

Active Ingredients New drugs Approval as generic drugsb) Pharmaceutical equivalent6) US FDA Guidance3) EMEA4)
1 Valsartan X O O O O
2 Bevantolol HCI O X X X X
3 Cilostazol X O O O O
4 Pilsicainide HCI O X X X X
5 Acipimox O X X X X
6 Fluvastatin Sodium O X O O O
7 Rosuvastatin Calcium O O O O O
8 Ezetimibe O X O O O
9 Olmesartan medoxomil O O O O O
10 Pitavastatin Calcium O O O O O
11 Cadralazine O X X X X
12 Bosentan O X X O O
13 Aliskiren Hemifumarate O X X O O
14 Ivabradine HCI O X X O X
15 Dronedarone HCI O X X O X
16 Lacidipine X O O X O
17 Limaprost O O O X X
18 Cilnidipine O O O X X
19 Cilazapril X O O X O
20 Acetyl-l-Carnitine O O O X X
21 Lercarnidipine HCI X O O X O
22 Benidipine HCI O O O X O
23 Imidapril HCI O O O X O
24 Ibudilast O O O X X
25 Triflusal O O O X X
26 Clopidogrel O O O O O
27 Atorvastatin X O O O O
28 Amlodipine X O O O O
29 Irbesartan O O O O O
30 Nifedipine SRc) X O O O O

b) This data is effective as of November 2011 in Korea. c) Slow-release form.