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Scientific Issues in Botanical Drug Product Development

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Scientific Issues in Botanical Drug Product Development Central Annals of Biometrics & Biostatistics Review Article *Corresponding author Shein-Chung Chow, PhD, Professor of Biostatistics and Bioinformatics, Duke University School of Medicine, 2424 Scientific Issues in Botanical Erwin Road, Suite 1102, Room 11068, Durham, NC 27710, USA, Email: Submitted: 06 June 2014 Drug Product Development Accepted: 07 January 2015 Shein-Chung Chow1* and Annpey Pong2 Published: 09 January 2015 1Duke University School of Medicine, North Carolina Copyright 2Merck Research Laboratories, New Jersey © 2015 Chow et al. OPEN ACCESS Abstract Keywords In recent years, as more and more innovative drug products are going off patents, the search for new medicines such as botanical drug products that can treat • Traditional Chinese herbal medicine critical and/or life-threatening diseases has become the center of attention of many • Dynamic balance or harmony pharmaceutical companies and research organizations such as the United States • Utilization ratio of the extracts (URE) National Institutes of Health (NIH). A botanical drug product is often recognized as • Experience-base clinical practice a traditional Chinese (herbal) medicine (TCM). The use of TCM in humans for treating • Matching placebo various diseases has a history of a few thousand years, although not much convincing scientific evidence (documentations) regarding clinical safety and efficacy are available. Thus, how to effectively and scientifically develop a promising TCM the Western way has become an important issue in public health. The purpose of this article is to provide a comprehensive overview regarding scientific and/or regulatory issues that are commonly encountered in botanical drug product or TCM development. These issues include, but are not limited to, intellectual property (IP), variation (or consistency) in raw materials, component-to-component interactions, animal studies, matching placebo and calibration of study endpoints in clinical trials, packaging insert, and transition from experience-base to evidence-base clinical practice. INTRODUCTION diagnostic procedure (i.e., inspection, auscultation and olfaction, interrogation, and pulse taking and palpation), criteria for In recent years, as more and more innovative drug products are going off patents, the search for new or alternative medicines such as botanical drug products that can treat critical and/or life- aevaluation TCM). of safety and efficacy in clinical trials, and treatment threatening diseases has become the center of attention of many (i.e., fixed dose for a Western medicine versus a flexible dose for pharmaceutical companies and research organizations such as The purpose of this article is multifold. First, it is to provide the United States National Institutes of Health (NIH). Botanical a comparison between a WM (e.g., chemical drug product) a drug products are often referred to as traditional Chinese herbal traditional TCM (e.g., botanical drug product) in terms of the fundamental differences. Second, it is to provide an overview of medicine (TCM). This leads to the development of TCM, especially regulatory requirements for botanical drug product development for those intended for treating critical and/or life-threatening based on a guidance published in 2004 [1]. Finally, it is to discuss diseases such as cancer. The use of TCM in humans for treating various diseases has a history of a few thousand years, although encountered during the development of a botanical drug product orcritical TCM. scientific These issues and/or include, regulatory but are issues not limited that areto, intellectualcommonly not much convincing scientific evidence (documentations) property (IP), variation (or consistency) in raw materials, component-to-component interactions, animal studies, regarding clinical safety and efficacy are available. Thus, how Western way has become an important issue in public health. matching placebo and calibration of study endpoints in clinical to effectively and scientifically develop a promising TCM the A Western medicine (WM) (e.g., a small molecular chemical drug product) often contains a single active ingredient, while evidence-base clinical practice. trials, packaging insert, and transition from experience-base to a TCM (e.g., a botanical drug product) usually consists of multiple active and inactive components. These multiple active and inactive components may not be characterized and their for Inapproval the next pathway section, offundamental a botanical differences drug product between (or TCM)WMs relationships are usually unknown. Thus, in practice, it is of great and TCMs are briefly described. FDA’s regulatory requirements issues that are commonly encountered during the development, Western way due to some fundamental differences between a WM review,are reviewed and regulatory in Section approval 3. Section process 4 provides of a TCM. some Concluding scientific andconcern a TCM. that These whether fundamental a TCM can differences be scientifically include evaluated differences the remarks regarding Westernization and/or modernization of TCM in medical theory, mechanism and practice, techniques of development are provided in the last section. Cite this article: Chow SC, Pong A (2015) Scientific Issues in Botanical Drug Product Development. Ann Biom Biostat 2(1): 1012. Chow et al. (2015) Email: Central FUNDAMENTAL DIFFERENCES Zang (or Yin organs) include heart (including the Fu As indicated by Chow and Liu (2008) [2], the process for (or TheYang five organs) include gall bladder, stomach, large intestine, pharmaceutical/clinical research and development of a chemical smallpericardium), intestine, lung, urinary spleen, bladder, liver, andand threekidney, cavities while (i.e.,the sixchest, drug product or WM is well established, and yet it is a lengthy epiastrium, and hypogastrium). Zang organs can manufacture and costly process. This lengthy and costly process is necessary and store fundamental substances. These substances are then transformed and transported by Fu organs. TCM treatments of the drug product under investigation. For pharmaceutical/ involve a thorough understanding of the clinical manifestations to ensure the efficacy, safety, quality, stability and reproducibility clinical research and development of a botanical drug product (or of Zang-Fu organ imbalance, and knowledge of appropriate TCM), one may consider directly applying this well-established acupuncture points and herbal therapy to rebalance or maintain process. However, this process may not be feasible due to some the balance of the organs. The channels and collaterals are the fundamental differences between a chemical drug product representation of the organs of the body. They are responsible (which often contain a single active ingredient) and a botanical drug product (or TCM) which often consists of multiple active and body. inactive components. Some fundamental differences between a for conducting the flow of energy and blood through the entire WM and a TCM are summarized in Table 1 (see also, Chow, Pong, The elements of TCM can also help to describe the etiology of described below. disease including six exogenous factors (i.e., wind, cold, summer, and Chang, 2006 [3]). These fundamental differences are briefly Medical Theory and Mechanism factors.dampness, Once dryness, all of theand information fire), seven emotionalare collected factors and (i.e.,processed anger, intojoy, worry,a logical grief, and anxiety, workable fear, diagnosis, and fright), the and traditional other pathogenic Chinese TCM has a long history of holistic medical system encircling medical doctor can determine the treatment approach. Chinese herbal medicines, acupuncture, massage, and therapeutic Under the medical theory and mechanism described above, the entire scopeQi-gong of human (the experience. practice of internalIt combines air) andthe Tai-gieuse of Chinese doctors believe that all of the organs within a healthy for both treatment and prevention of disease. With its unique subject should reach the so-called global dynamic balance or theoriesexercise suchof etiology, as diagnostic systems, and abundant historical harmony among organs. Once the global balance is broken literature, TCM itself consists of Chinese culture and philosophy, at certain sites such as heart, liver or kidney, some signs and clinicalChinese practice doctors experience, believe andhow the a TCM use offunctions many medical in the herbs.body is symptoms then appear to reflect the imbalance at these sites. Zang and An experienced Chinese doctor usually assesses the causes of Fu, and information regarding channels and collaterals. Eight global imbalance before a TCM with flexible doses is prescribed based on the eight principles, five-element theory, five personalized (or individualized) medicine approach. principles consist of Yin and Yang (i.e., negative and positive), to fix the problem. This approach is sometimes referred to as a six Shi and Xu (i.e., weak and Medical Practice strong). The eight principles help Chinese doctors to differentiate syndromecold and hot, patterns. external For and instance, internal, peopleand with Yin will develop of certain diseases could lead to a different diagnosis and disease in a negative, passive, and cool way (e.g., diarrhea and Different medical perceptions regarding signs and symptoms back pain), while people with Yang will develop disease in an aggressive, active, progressive, and warm way (e.g., dry eyes, thetreatment disease for of thethirsty diseases reduction under
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