Development of Plant-Derived Mixtures as Botanical Drugs: Clinical Considerations

Abstract

In response to various drug-related disasters, the requirement for demonstration of safety for marketed drug products was first established in the Federal Food, Drug, and Cosmetic Act (FDCA) of 1938. The requirement for demonstration of a drug’s effectiveness through adequate and well-controlled clinical investigations was added in the 1962 Kefauver-Harris Amendments of the FDCA. Since then, FDA has published several guidances which describe how clinical trials may be designed to adequately demonstrate the safety and efficacy of drug products and protect human subjects from unreasonable harms. FDA has issued Guidance for Industry on Botanical Drug Products (2004) and Botanical Drug Development (2016) that described how plant-derived mixtures, including multiple-herb combinations, may be developed as new drugs without further purification. Previous human experience may be used to support phase 2 clinical trials in patients, thus skipping “first-in-human” phase 1 tolerability studies. For drugs with prior human experience, animal toxicological studies may also be delayed to later phases of drug development. In phase 3 trials, patient exposure to multiple batches and multiple doses of botanical drug products is recommended in order to derive more reliable quality specifications and ensure therapeutic consistency for future marketed batches. Two botanical new drug applications (NDAs), Veregen ® (sinecatechins), for the treatment of genital warts), and Mytesi®, formerly Fulyzaq ® (crofelemer), for the treatment of HIV-related diarrhea, were approved by FDA in the past decade. The bases for these approvals will be described and will serve as successful examples to guide and encourage further development of botanicals as new drugs. Published clinical and nonclinical studies of two herbal medicines, Artemisia annua and Pelargonium sidoides , will be discussed to illustrate some of the challenges faced in clinical trial design and data reporting. Additional challenges in the development of botanical products derived from multiple herbs as fixed-dose drug combinations will also be discussed.