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Food and Chemical Toxicology
Volume 46, Issue 8, August 2008, Pages 2606-2610
 
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doi:10.1016/j.fct.2008.05.029    
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Published by Elsevier Ltd.

Review

Current regulatory toxicology perspectives on the development of herbal medicines to prescription drug products in the United States

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Kuei-Meng WuCorresponding Author Contact Information, a, E-mail The Corresponding Author, Hanan Ghantousa and Debra B. Birnkranta

aCenter for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States


Received 24 April 2008; 
accepted 26 May 2008. 
Available online 4 June 2008.

Abstract

Toxicological studies constitute an essential part of the effort in developing an herbal medicine into a drug product. The US food and drug administration (FDA) published a guidance to assist academic and industry sponsors in the development of this unique group of drug products, and has recently approved an new drug application (NDA) based on green tea extract (Veregen®) for topical treatment of genital and perianal warts. In this article, current regulatory views on issues related to requirements and recommendations on various types of nonclinical toxicity studies in support of clinical trials and filing an NDA for a herbal medicine, including pharm/tox aspects of green tea extract (Veregen®) NDA, are discussed. Topics include nonclinical pharmacology/toxicology perspectives on herbal nomenclature and its identification, previous human experience and initial clinical trial proposal, regulatory aspects of acute toxicity studies, chronic toxicity studies, mutagenicity studies, reproductive toxicity studies, and carcinogenicity studies on botanicals. Certain regulatory review-related issues are also presented. It is anticipated that through a proactive two-way communication between the Agency and the sponsor, toxicological development of botanical drug product can be significantly facilitated.

Keywords: Herbal; Botanical; Carcinogenicity; Genotoxicity; Reproductive toxicity; Regulatory toxicology

Article Outline

1. Introduction
2. Importance of herbal nomenclature for botanical drug products
3. Waiver of toxicology studies for initial clinical trial on herbal medicine intended to be used as prescription drug
3.1. Previous human experience and existing animal toxicity data
3.2. The “Initial” clinical trial
4. Toxicological studies on herbal medicine supporting advanced clinical trials, NDA submission and premarketing approval for its intent as drug
4.1. Acute toxicology studies
4.2. Chronic toxicology studies
4.3. Nine-month nonrodent mammalian toxicity studies
4.4. Animal toxicokinetic and pharmacokinetic studies
4.5. Genotoxicity studies
4.6. Reproductive toxicology studies
4.7. Carcinogenicity studies
5. Regulatory toxicology review issues related to herbal medicine IND and NDA applications
5.1. Dosing and duration of the proposed initial clinical trial exceed those recommended traditionally/historically
5.2. Claims of “nontoxicity”, lack of information on target organ of toxicity, and unaddressed equivalency to daily amount of raw herbs used in traditional practice
5.3. Use of animal products and endangered species
6. Summary
Conflict of interest statement
Acknowledgements
Further Reading
References

Corresponding Author Contact InformationCorresponding author. Tel.: +1 301 796 9880.

Food and Chemical Toxicology
Volume 46, Issue 8, August 2008, Pages 2606-2610
 
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