a b s t r a c tToxicological 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 Ò ) 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 Ò ) 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 reviewrelated 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.Published by Elsevier Ltd.
The distribution of trichloroethylene (Tri) and tetrachloroethylene (Tetra) and their metabolites have been studied in pregnant mice by means of whole‐body autoradiography (14C‐labelled Tri and Tetra) and gas chromatography, with special emphasis on possible uptake and retention in the foetoplacental unit. Volatile (non‐metabolized) activity appeared at short intervals after a 10 min. or 1 hr inhalation period in foetus and amniotic fluid. Most notable, however, was a strong accumulation and retention (peak at 4 hrs) in amniotic fluid of the metabolite trichloroacetic acid (TCA) after inhalation of either of the solvents. The main metabolite of Tri, trichloroethanol (TCE) (or conjugates), did not accumulate specifically as compared to maternal plasma. TCA infused intravenously in the maternal plasma was accumulated in amniotic fluid, but less pronounced than after Tri and Tetra inhalation, indicating that some metabolism of Tri and Tetra to TCA may occur in the foetoplacental unit. The results suggest that TCA may be transported to the foetus partly paraplacentally through foetal membranes and amniotic fluid, with the possibility of foetal swallowing or absorption through the skin. Foetal urinary activity also suggests that circulation between foetus and amniotic fluid may contribute to the long‐term retention in the foetoplacental unit. In the mother, after inhalation exposures, and in intraperitoneally injected newborn mice, non‐extractable radioactivity was found in the respiratory tract, liver, and kidney, indicating binding to these organs through metabolism.
Toxicological studies constitute an essential part of the effort in developing a botanical supplement into a drug product. The US Food and Drug Administration recently published a draft guidance and established a special botanical review team to assist academic and industry sponsors to manage this and other regulatory considerations related to this unique group of drug products. In this article, the current state of regulatory viewpoints on issues related to requirements and recommendations of various types of nonclinical toxicity studies in support of advanced phases clinical trials and filing a New Drug Application of a botanical are discussed. Topics include nonclinical pharmacology/toxicology view of previous human experience and initial clinical trial, regulatory perspectives on 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 2-way communication between the Agency and the sponsor, toxicological development of botanical drug product can be significantly facilitated.
Genotoxicity testing is an important part of preclinical safety assessment of new drugs and is required prior to Phase I/II clinical trials. It is designed to detect genetic damage such as gene mutations and chromosomal aberration, which may be reflected in tumorigenic or heritable mutation potential of the drug. Botanical new drugs in the U.S. are entitled to a waiver for preclinical pharmacology/toxicology studies, including genotoxicity testing, in support of an initial clinical trial under IND, contingent on previous human experience. Recently, ethical concerns have been raised over conducting Phase I/II clinical trials of new drugs with positive genotoxicity findings in healthy volunteers. Although the relevance of this issue to patients, as opposed to healthy volunteers, depends on the drug's indication, duration of treatment, and specific findings related to the assays, the regulatory view is to avoid exposing patients to genotoxic compounds unnecessarily in clinical trials. This philosophy may impact on herbal supplement marketing and botanical drug development, in that genotoxicity data are often lacking while consumers are exposed to the herbal supplement, or healthy volunteers are tested in an initial Phase I/II clinical trial on the botanical drug. This paper presents results of a survey conducted on genotoxicity data in botanical INDs submitted to the Agency and discusses the significance of this information. The information presented indicates that the sponsors of botanical INDs have increasingly recognized the importance of genotoxicity information and may have prioritized its acquisition in their strategic drug development programs.
The timing of carcinogenicity studies in parallel with the clinical development of anti-human immunodeficiency virus (HIV) drugs has been flexible for most cases in the past. This includes postponement of the initiation of the studies and submission of final audited reports to the US Food and Drug Administration (FDA) for a new drug application (NDA) approval. We address this regulatory practice for anti-HIV drugs for which, in the past, there had been no effective treatment. We also examine the correlation of genotoxicity data with carcinogenicity data for the varied subclasses of anti-HIV drugs. We suggest that this regulatory policy regarding the timing of carcinogenicity testing does not compromise the safety standards of FDA's drug evaluation and the approval process. The policy does facilitate availability of these agents to meet the medical needs of the target population. Our analysis on the profile of carcinogenicity findings of anti-HIV drugs shows trends of class effects. Additionally, both carcinogenicity and genotoxicity data show significant correlations, which provide useful insights into issues involving these 2 important areas of toxicological investigations.
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