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Few therapeutic specialty molecules from in vitro cultures beyond paclitaxel have come to market and although other more complex products like ginseng have also appeared, success has been limited. Often it is not the science that is limiting, but rather regulatory issues that limit considerations of potential products mainly because of costs in getting the product to market. Here we discuss broader thinking of such specialty molecules in the form of dietary supplements, nutraceuticals, herbal medicines, botanical drugs, and pure molecules along with potential complex products from a regulatory standpoint and especially within the realm of approved botanical drugs, e.g., Veregen and Fulyzaq, that have new drug applications (NDAs). The United States food and drug administration (US FDA) regulatory categories are used to provide examples of alternative product options that could prove useful for taking specialty molecules to market.

On November 3, 2014, in Bethesda, MD, the Office of Cancer Complementary and Alternative Medicine of the National Cancer Institute held a meeting to examine the potential utility and feasibility of establishing an international consortium for Chinese medicine and cancer. There is significant interest in the West in using components of Chinese medicine (CM) —such as botanicals and herbal medicines, acupuncture and acupressure, and qigong—in the field of oncology, as potential anticancer agents, for symptom management, and to improve quality of life. The proposal for a consortium on CM came from the Chinese Academy of Chinese Medical Sciences, with the aims of improving scientific communications and collaborations and modernizing the studies of CM for cancer. The US National Cancer Institute’s Office of Cancer Complementary and Alternative Medicine agreed to work with Chinese Academy of Chinese Medical Sciences to explore the feasibility of establishing an international consortium for Chinese medicine and cancer. At the meeting, participants from the United States, China, Canada, Australia, and Korea discussed issues in CM and cancer research, treatment, and management, including potential mechanisms of action, proof of efficacy, adverse effects, regulatory issues, and the need for improving the quality of randomized clinical trials of CM treatments and supportive care interventions. Presented in these proceedings are some of the main issues and opportunities discussed by workshop participants.

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.

Black cohosh, red clover, hops, and chasteberry are botanicals commonly used to alleviate menopausal symptoms in the US, and are examined in this study as part of a FDA Office of Women's Health research collaboration to expand knowledge on the safety of these botanical products. Computational approaches using classic (quantitative) structure-activity relationships ((Q)SAR), probabilistic reasoning, machine learning methods, and human expert rule-based systems were employed to deliver human hepatobiliary adverse effect predictions. The objective is to profile and analyze constituents that are alerting for the human hepatobiliary adverse effects. Computational analysis of positively predicted constituents showed that common structural features contributing to the hepatobiliary adverse effect predictions contain phenolic, flavone, isoflavone, glucoside conjugated flavone and isoflavone, and 4-hydroxyacetophenone structures. Specifically, protocatechuic acid from black cohosh, benzofuran and 4-vinylphenol from chasteberry, and xanthohumol I from hops were botanical constituents predicted positive for liver toxicity endpoints and were also confirmed with literature findings. However, comparison between the estimated human exposure to these botanical constituents and the LOAEL and NOAEL in published animal liver toxicology studies for these constituents demonstrated varying margins of safety. This study will serve as regulatory decision support information for regulators at the FDA to help with the process of prioritizing chemicals for testing.

Although new botanical drugs pose many challenges for both industry and the FDA, approval of the first botanical prescription drug shows they can be successfully met.

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.

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.

In an effort to discover new chemotherapeutic/chemopreventive agents from natural sources, brusatol (1) was found to induce HL-60 cellular differentiation, accompanied by strong antiproliferative and cytotoxic effects. A series of natural and semisynthetic quassinoids (1-48) was designed to effect both antiproliferative and differentiation-inducing properties. Compounds were assessed in vitro using the HL-60 promyelocytic cell model. Changes in activity due to structural modification of the core structure glaucarubolone (24) were consistent with activities reported in other cell systems. However, the following were novel SAR findings: (1) semisynthetic analogues with a hydroxylated ring at the beta-position of the ester side chain at C-15 were able to induce cellular differentiation at concentrations lower than those inducing cell growth arrest, and (2) quassinoids inhibiting DNA synthesis with greater efficacy than reducing cellular viability possessed alkyl substitutions at the alpha-position of the C-15 ester side chain. Analogues from this latter group and brusatol (1) and bruceantin (2) inhibited dimethylbenz(a)anthracene-induced preneoplastic lesion formation in a mouse mammary organ culture. The novel finding of 1 and glaucarubolone analogues as potent inducers of differentiation leads to potential novel applications in the field of cancer.