Botanical Drug Development: Waiver of Preclinical Pharm/Tox Studies and Importance of Initial Cinical Trial Design

Development of botanical drug products in the U.S. may be entitled for a waiver of preclinical Pharm/Tox (P/T) studies prior to an initial clinical trial, contingent upon existing previous human experience. The regulatory perspective for this measure is to allow the sponsor to conduct a well‐designed Phase I/II trial to detect initial signals of efficacy without prior animal studies. Based on botanical INDs submitted to the FDA, the “initial” trials proposed have some of the following design characteristics: (1) the treatment duration for certain indications often lasted longer than a typical Phase I/II trial (e.g., ≥6 months for hepatitis and HIV); (2) the dose proposed sometimes far exceeded that recommended historically or that used under dietary supplement, without supporting P/T studies; (3) the sample size was limited and dosage often arbitrarily selected without a supporting dose ranging trial. These issues on the initial trial design, particularly in regard to the sample size, duration and dosage, may compromise the study, resulting in outcomes that may inadequately address the original question as to whether the botanical is efficacious, and mislead conclusions on the botanical's pharmacological effects in patients. These variables and factors could be part of the reasons why most of the botanical INDs submitted to the FDA become inactive, and do not progress to the advanced phase of drug development.