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. scientificThese issues and/or include, regulatory but are issuesnot limited that areto, intellectual commonly 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 In approval the next pathway section, of fundamental 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 Thesewhether 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 pericardium),small intestine, lung, urinary spleen, bladder, liver, and and three kidney, cavities while (i.e., the six chest, 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 internal It combines air) and the Tai-gie use 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 by study.Chinese For doctors. example, The the disease signs ofand type symptoms 2 diabetes of istype not 2 recognized diabetic subjects by Chinese could medical be classified literature as tinnitus, and night sweats). The five elements (earth, metal, although they have the same signs and symptoms as the well- human body. Each element operates in harmony with the others. known disease of thirsty reduction. This difference in medical water, wood, and fire) correspond to particular organs in the perception and practice has an impact on the diagnosis and Table 1: Fundamental differences between a WM and a TCM. treatment of the disease. Traditional Chinese Herbal Description Western Medicine In addition, we tend to see therapeutic effect of WMs sooner Medicine Active than TCMs. TCMs are often considered for patients who have Single Multiple ingredient chronic diseases or non-life-threatening diseases. For critical and/or life-threatening diseases such as cancer or stroke, TCMs are often used as the second line or third line treatment with no Dose Objective;Fixed validated Subjective;Flexible not validated procedure other alternative treatments. In many cases such as patients with later phase of cancer, TCMs are often used in conjunction with TherapeuticDiagnostic Well-established Not well-established WMs without the knowledge of the primary care physicians. Global dynamic Medical Techniques of Diagnosis index balance/harmony mechanism among organs The Chinese diagnostic procedure for patients with certain Medical Specific organs diseases consists of four major techniques, namely, inspection, Evidence-base perception auscultation and olfaction, interrogation, and pulse taking and Statistics Population Experience-baseIndividual palpation. All these diagnostic techniques aim mainly at providing

Ann Biom Biostat 2(1): 1012 (2015) 2/4 Chow et al. (2015) Email: Central an objective basis for differentiation of syndromes by collecting an assay is necessarily developed to quantitate the potency of the symptoms and signs from the patient. Inspection involves (healthy volunteers) for pharmacological activities. Unlike the WMs,drug. TheTCMs drug usually is then consist tested of on multiple animals components for toxicity, andwith humans certain observing the patient’s general appearance (strong or weak, fat or relative proportions among the components. As a result, the thin), mind, complexion (skin color), five sense organs (eye, ear, typical approach for evaluation of single active ingredient for WM andnose, cough. lip, and Olfaction tongue), involves secretions, smelling and the excretions. breath and Auscultation body odor. is not applicable. involves listening to the voice, expression, respiration, vomit, In practice, one may suggest evaluating the TCM component and the general condition including history of the present disease, by component. However, this is not feasible due to the following pastInterrogation history, personal involves life asking history, questions and family about history. specific Pulse symptoms taking and palpation can help to judge the location and nature of a of individual components are often not tractable. Thus, the disease according to the changes of the pulse. pharmacologicaldifficulties. First, activitiesin practice, of theseanalytical components methods are for not quantitation known. It The Chinese diagnostic procedure of inspection, auscultation should be noted that the component which comprises the major and olfaction, interrogation, and pulse taking and palpation is proportion of the TCM may not be the most active component. subjective, with large between rater variability (i.e., variability On the other hand, the component that has the least proportion from one Chinese doctor to another). This subjectivity and of the TCM may be the most active component of the TCM. In practice, it is not known which relative proportions among these evaluability but also the prescribability of TCM. For evaluation of components can lead to the optimal therapeutic effect of the avariability WM, objective will criteria have an based impact on some not well-established only on the patient’s clinical TCM. In addition, the relative component-to-component and/or component by food interactions are usually unknown, which may rate (i.e., complete response plus partial response based on tumorstudy endpointssize) is considered are usually a valid considered. clinical endpointFor example, for evaluating response the TCM. have an impact on the evaluation of clinical efficacy and safety of Fixed Dose Versus Flexible Dose diagnostic procedure for evaluation of a TCM is very subjective. Theclinical use efficacy of a of subjective oncology Chinesedrug products. diagnostic Unlike procedure WMs, Chinese has raised the following issues. First, it is a concern whether the a 10 mg tablets or capsule). On the other hand, since a TCM subjective Chinese diagnostic procedure can accurately and consistsMost of WMs multiple are usually components administered with possible in a fixed varied dose relative (say proportions among the components, a Chinese doctor usually investigation. Thus, it is suggested that the subjective Chinese prescribes the TCM with different relative proportions of the diagnosticreliably evaluate procedure clinical should efficacy be validated and safety in terms of the of its TCM accuracy, under multiple components based on the signs and symptoms of the precision, and ruggedness before it can be used in TCM clinical patient according to his/her best judgment following a subjective trials. A validated Chinese diagnostic procedure should be able evaluation based on the Chinese diagnostic procedure. Thus, differenceto detect a when clinically there significant is no difference. difference if the difference truly unlike a WM which is prescribed as a fixed dose, a TCM is often exists. On the other hand, it is not desirable to wrongly detect a prescribed as an individualized flexible dose. In clinical trials, evaluation is usually based on some validated to minimize the between subject (or inter-subject) variability, The approach of WM with a fixed dose is a population approach tools (instruments) such as laboratory tests. Test results are then evaluated against some normal ranges for abnormality. Thus, to minimize the variability within each individual. In practice, it is while the approach to TCM with an individualized flexible dose is it is suggested that the Chinese diagnostic procedure must be validated in terms of validity and reliability, and its false positive a concern whether an individual flexible dose is compatible with and false negative rates, before it can be used for evaluation of whicha Western may evaluation vary from ofone the Chinese TCM. An doctor individualized to another. flexible As a result, dose depends heavily upon the Chinese doctor’s subjective judgment, clinicalTreatment efficacy and safety of the TCM under investigation. subject variability, the variability from one Chinese doctor to although an individualized flexible dose does minimize intra- TCM prescriptions typically consist of a combination of another (i.e., the doctor-to-doctor or rater-to-rater variability) several components. The combination is usually determined could be huge, and hence non-negligible. based on the medical theory of global dynamic balance (or REGULATORY REQUIREMENTS harmony) among organs, and the observations from the Chinese diagnostic procedure. The use of Chinese diagnostic procedure In 2004, the United States (US) Food and Drug Administration The treatment is to re-install the balance among these organs. is to find out what caused the imbalance among these organs. (FDA) published a guidance on botanical drug products, which explains when a botanical drug may be marketed under an over- achieve the balance. This concept leads to the concept of so-called the-counter drug monograph, when an FDA regulations require personalizedThus, the dose (or and individualized) treatment duration medicine, are flexible which in minimizes order to approval for marketing of New Drug Application (NDA), and intra-subject variability. Most WMs contain a single active products currently lawfully marketed as foods in US [1]. To when Investigational New Drug Applications (INDs) for botanical ingredient. After drug discovery, an appropriate formulation (or provide a better understanding of the review process in Center dosage form) is necessarily developed so that the drug can be for Drug Evaluation and Review (CDER) for INDs and NDAs delivered to the site action in an efficient way. At the same time, for botanical drug products, the CDER of FDA also published Ann Biom Biostat 2(1): 1012 (2015) 3/4 Chow et al. (2015) Email: Central

Manual of Policies and Procedures (MAPP): Review of Botanical recommendsDrug Products, that which the describesguidance entitledthe review Guidance process for in Industry CDER for – INDs for and Phase NDAs 2 forand botanical Phase 3 Studies, drug products Chemistry, [4]. Manufacturing, The MAPP [4] and Controls Information be consulted for preparing chemistry, manufacturing, and control (CMC) information that would be submitted for phase 2 and phase 3 studies required for botanical drug product development conducted under INDs in US [5]. productsAs indicated should include in the protocols, 2003 FDA CMC, guidance, pharmacological similar and to conventional drug development, the INDs for botanical drug the product (see Table 2). Requirements for CMC and non- clinicaltoxicology safety information, assessment and are previous given in human(Table 3) experience and (Table with 4), respectively. Table 3 indicates that animal safety test needs to be performed. This requirement, however, is referred to an acute placeboanimal toxicity used must test be applied described. only Forto injectable phase 3 clinical drug product. studies, Forthe matching placebo, the FDA requiresg information that the that components (i) description of any of

FDA requires that the followin Tableproduct 2: and documentation of human experience, (ii) chemistry,

Cover Basicsheet Format for IND for Botanical Drug Products. Table of contents Introductory statement and general investigational plan

Protocols Investigator’s brochure Chemistry, manufacturing, and controls Figure 1 drug product. Flowchart for approval pathway of an IND for a botanical

Pharmacological and toxicology information manufacturing, and controls, (iii) non-clinical safety assessment, (iv) bioavailability and clinical pharmacology, and (v) clinical TablePrevious 3: CMC human Requirements experience for INDs with of Botanical the product Drug Products considerations must be provided. Figure 1 provides a summary Botanical raw material Botanical drug substance and product Currentfor information Review required Process for an for IND Botanical of botanical Products drug products. Animal safety test Regulatory review of botanical submission include CMC information review, clinical pharmacology/biopharmaceutics Placebo Labeling information review, and medical/statistical information review. information review, non-clinical pharmacology and toxicology Environmental assessment review team (BRT) to assist the review divisions for review of theFor botanical each botanical submission. submission, The BTR FDA review establishes covers (i) a biology botanical of Table 4: Requirements for Non-clinical Safety Assessment species, (ii) pharmacology of the botanical product-activity/ the medicinal plants-identification, potential misuse of related Repeat-dose general toxicity studies relevancetoxicology to in current old documents setting. andThe newbotanical tests, team (iii) priorwill perform human Nonclinical pharmacokinetic/toxicokinetic studies experiences with the botanical product-past clinical use and Reproductive toxicology Carcinogenicity studies applications,pharmacognosy the reviewbotanical throughout team will the not IND have and direct NDA contacts process with and Genotoxicity studies thebotanical-specific sponsors. However, medical the review. botanical For team issues may related respond to directlyspecific to general inquiries related to the botanical guidance and other Regulatory consideration Special pharmacology/toxicology studies relevant policies/procedures. Note that all communications will

Ann Biom Biostat 2(1): 1012 (2015) 4/4 Chow et al. (2015) Email: Central

Figure 2 Flowchart for regulatory approaches for marketing botanical drug products.

describes regulatory approaches for marketing botanical drug be transmitted through the review division. A flow chart that constituents are not always well defined. In many cases, the products is given in (Figure 2). its biological activity well characterized. A new botanical drug (containingactive constituent multiple in chemicala botanical constituents) drug is not may identified, qualify nor as is a Botanical Products Versus Chemical Drugs Although regulatory requirements for botanical products are active ingredients in botanicals are optional and not required. Innew the chemical initial stageentity. of Both clinical purification studies ofand a botanicalidentification drug, of itthe is similar to those for chemical drugs in principle, there are many generally not necessary to identify the active constituents or differences in policy issues, which are summarized below: Purification and Identification other biological markers or to have a chemical identification Botanical drugs are derived from vegetable matter and strengthand assay by for dry a weightparticular (weight constituent minus wateror marker. or solvents) Identification can be acceptableby spectroscopic alternatives. and/or chromatographic fingerprinting and are usually prepared as complex mixtures. Their chemical Ann Biom Biostat 2(1): 1012 (2015) 5/4 Chow et al. (2015) Email: Central

Test and Control with variations in relative contents of multiple plant ingredients tailored for each patient. A sponsor may not submit a separate

treated for the same indication. Studies can be designed to take on aBecause combination of the complex of tests nature and controls of a typical to ensure botanical the drug identity, and intoIND for account every change individualized in composition, treatments. if similar Multiple patients formulations are being purity,the lack quality, of knowledge strength, of its potency, active andconstituent(s), consistency FDA of botanicalmay rely drugs. These tests and controls include (i) multiple tests for drug substance and drug product (e.g., spectroscopic and/or forcan usingbe included multiple in one formulations IND if they andare being the criteria studied used under to a assignsingle patientsclinical trial.to different It is important treatment that regimens. the IND provide the rationale markers, and biological assay), (ii) raw material and process controlschromatographic (e.g., strict fingerprints, quality controls chemical for assay the of botanical characteristic raw Toxicity materials and adequate in-process controls), and (iii) process Many medicinal plants with therapeutical potential are validation (especially for the drug substance). Raw material and environmental issue: Because the botanical drug products quite toxic. Well-known examples of safety issues concerning is a more complicated issue than that of non-botanicals. Plant botanicals include the nephrotoxicity associated with herbal are allowed to remain as complex mixtures, quality consistency associated with comfrey products containing pyrrolizidine materials used in the production of botanical drug products preparations containing aristolochic acid and the hepatotoxicity nervous system effects associated with yohimbe and the to contamination, deterioration, and variation in composition alkaloid. Other examples include the cardiovascular and central andoften properties.are not completely In many characterized cases, the and active defined constituent or are prone in a inhepatotoxicity the intended associated patient population, with germander clinical trialsand chapparal. may be allowed When well characterized. Therefore, in contrast to the situation with the potential benefit of an investigational drug outweighs its risk botanical drug is not identified, nor is its biological activity to ensure the quality of a botanical drug by controlling only the toPrior proceed Human under Experience an IND. correspondingsynthetic or highly drug substance purified drug and products,drug product. it may To ensure be difficult that The Guidance also stipulates that because many botanicals a botanical drug product used in clinical trials is of consistently have been used as medicine in alternative medical systems good quality, and that sufficient information exists to meet the product testing, appropriate quality controls for the botanical raw for long time, the prior human experiences may substitute for requirements, the sponsor should have, in addition to final animal toxicology studies in the preliminary safety evaluation drug substance and product to that of botanical raw material, and of IND studies. How these human data, mostly not of modern materials. It became necessary to extend the control of botanical was not clearly described in the Guidance. The Agency recognizes in some cases, to the agricultural aspects of growing/harvesting scientific quality, can be useful to support an NDA application medicinal plants by following Good Agricultural and Good documented in many different forms and sources, some of which Collection Practice (GAP and GCP) for starting materials of herbal that prior human experience with a botanical product can be The sponsor is encouraged to provide as much data as possible, environment-related aspects of a requested action, especially one may not meet the quality standards of modern scientific testing. thatorigin. involves FDA encourages harvesting earlya wild consultation species, to ensure with the that Agency planning on accept all available information for regulatory consideration. and the review team for the botanical drug IND generally will and decisions reflect environmental values, avoid delays later in case basis. It should be emphasized that, in reviewing botanical there could be more than one active constituent in a botanical drug FDA will assess the quality of the submitted data on a case-by- the process, and avoid potential conflicts. Bioavailability: Because or impossible to perform standard in vivo bioavailability and drugs, the Agency does not lower or raise the safety and efficacy or the active constituent may not be identified, it could be difficult drugs. pharmacokinetic studies. If this is not possible, the bioavailability standards for marketing approval that apply to purified chemical of a botanical drug could be based on clinical effects observed in Priority defer the in vivo bioavailability study requirement if a waiver or deferralwell-controlled is compatible clinical withtrials. the FDA protection may, for goodof the cause, public waive health. or FDA treats botanical and purified chemical drugs the same. FDA will assign the same level of priority to botanical drug products as to other drugs with respect to meeting with IND IND: FDA does not require that all studies submitted in an NDA be marketing approval there should be no difference between botanicalsponsors and and non-botanical NDA applicants. drugs. For The clinical Guidance data also to provides support (i.e.,conducted if they under are carried an Investigational out abroad). New The Drugclinical Application data generated (IND). Clinical studies need not necessarily be conducted under an IND two flow charts for: 1) the regulatory approaches for marketing conductedfrom these under studies good conducted clinical practices. without an However, IND can although be used an to botanical drug products (attachment B, FDA 2004 [1]), and 2) support an NDA if the studies were adequately designed and inthe this information paper (Figures to be 1,2) provided also to elucidate in an IND the for process a botanical of the drugnew (attachment A, FDA, 2004 [1]). The two flow charts are attached IND is not required by law in all cases, the sponsor is encouraged toIndividualized go through the IND Treatments process. topolicy. be developed With the release and get of into the FDAthe approvalnew guidance process. and Inapproval the near of In many cases, botanical therapies are highly individualized future,first botanical the botanical drug, more drugs and more will bebotanical accepted drugs by are mainstream predicted

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deriving from traditional knowledge, methods of treatments, drug industry will be tighter. medical field as a big family in drug chest. The competition in are not considered inventions under the current Taiwan Patent SCIENTIFIC ISSUES IN BOTANICAL DRUG (OR Law.products In Taiwan,and processes invention are patentable refers to [8]. the The creation first two of however, technical TCM) DEVELOPMENT concepts by utilizing the rule of nature; therefore, it needs to have In this section, a number of critical issues that are often encountered during the development of a botanical drug product patenting traditional medicines, the patenting of products and processessome degree of Chineseof technical herbal character. inventions Despite is not the a novel controversies idea. of

(orIntellectual TCM) are briefly Property discussed. (IP) In current practice, the dominant Western drug discovery process from natural products has the following goals that (i) it Song [6] indicated that innovation of TCM can be divided into is to isolate bioactive compounds for direct use as drugs, (ii) it is two categories: one is the self-innovation of TCM and the other to produce bioactive compounds of novel or known structures as is innovation based on knowledge and techniques of TCM. Both lead compounds for semi-synthesis to produce patentable entities innovations have been presented with different questions of intellectual property (IP) derived from past events. As Song [6] as pharmacologic tools, and (iv) it is to use the whole plant or pointed out, under market economy conditions where private partof higher of the activity plant as and/or a herbal lower remedy toxicity, [9]. In (iii) practice, it is toif theuse Chinese agents herbal invention is not a pure compound, then there are some intellectual property legal system should be established for therights protection are legitimate of the and innovation interests of must TCM. be Hence, maximized, not only a proper rules is the difference in the names used in the classics. Many plants of market economy but also intellectual property law must be havecomplexities different in names filing especiallya patent application. they are from The different first complexity sources. complied with. However, majority of self-innovation of TCM The lack of uniformity has not only created confusion, but also generally do not seek for protection of IP due to the nature of conservativeness of Chinese people and most importantly lack of Smallanthus Sonchifloius in the folk medicine and Saussyrea Lanicepresult in Hand-Mazzinconsistency in for the the classics development are two of TCM. different For example, types of confidenceHsiao [7] in pointedcurrent patentout that system in the for current IP protection. patent system; an plants with very different pharmacological uses but their names novelty, inventive step, industrial applicability and enablement. Aninvention invention has to has satisfy to pass the examiner the novelty in many test aspects before including proceeding its are similar in terms of Chinese language. The second complexity to other steps. Failure to satisfy the novelty requirement will chemicalrelates to compoundsthe crude materials (which and could the be difficulties identically in allocating reproduced), the render the invention non-patentable. In the past several decades, plantseffective are active living ingredients. organisms The that third vary complexity in characteristics is that unlike even novelty has barred many Chinese herbal medicines (products) from patentability because they are either based on traditional formulas or have the same medicinal use and are already within the same variety of plants. Another complexity is that available to the public. In practice, some interventions are impure substances are abundant in plants. Lastly, it is difficult to considered non-novel and hence not patentable. These situations proveVariation the pharmacological (Consistency) efficacy in Raw of ChineseMaterials herbal medicine. include (i) when the claimed medical uses can be deduced from One of the critical issues in TCM manufacturing is variation prior art based on a common mode of action, and (ii) when the in raw materials. The variation in raw materials, which may be claimed medical uses can be ascribed to pharmacological effects due to the fact that they come from different regions, climates, closely related to those in prior art. and time of harvest, could have a negative impact on the quality As indicated by the Taiwan Intellectual Property Office (TIPO) of the TCM and consequently the safety and efficacy of the TCM. as any creation of technical concepts by utilizing the rules of upon the combined effects of its components. Variation in Yan and Qu [10] indicated that the efficacy of a TCM depends nature.Guidelines Thus, for inventions Patent Examination, that are mere an invention discovery, is againstreferred the to chemical composition between batches of TCM has been always rule of nature, not using the rule of nature, or non-technical in characters are not considered as inventions. TIPO adopts the components, however, may or may not be correlated and may the deterring factor of achieving consistency in efficacy. These standard of absolute novelty in the sense that an invention have component-to-component interaction which will have an has to be new and nothing similar to those that have appeared impact on achieving optimal therapeutic effect of the TCM. In practice, unfortunately, the correlations among the components and their relative ratios for achieving optimal therapeutic effect are considered as prior art. Note that in patent law, novelty before the date of filing. For those are available to the public are often unknown. orderreflects to the transform basic principle something in property belonging law to that nature ownership or the public of an intervention is acquired by being the first in time to possess it. In domain, the discoverer has to transform the discovery into an Yan and Qu [10]well-designed indicated that proportion, batch mixing which process is referred can significantly reduce the batch-to-batch variation in TCM extracts search for prior art in relation to Chinese herbal medicines, TIPO by mixing them in a hasinvention established to demonstrate a database the of possession. classics and To traditional assist examiners formulas to to as utilization ratio of the extracts (URE). Yan and Qu [10] that are in the public domain. Along this line, there are several suggested an innovative and practical batch mixing method for possible types of end products of traditional Chinese medicine meetachieving the content an acceptable limits under efficiency an acceptable for manufacturing URE. Yan of and TCM Qu products by using a minimum number of batches of extracts to

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[10] indicated that URE is affected by the correlation between the contents of components. In practice, URE decreases with process. the increase in the number of targets and the relative standard optimization model and mixtures are created for the follow-up Remark: deviations of the contents. URE could be increased by increasing the number of storage tanks. Thus, to achieve an acceptable URE, The batch mixing process can significantly reduce the variation in the quality of TCM extracts among different batches by mixing them in a well-designed URE. The batch it is desirable to use up some batches of extracts in one mixing to mixing method proposed in this work uses a minimum number reduce the number of residual batches. These findings provide practical in industrial production. The impacts of the important of batches of extracts to meet the content limits, which is more reference standards for designing the batch mixing process. factors on URE were studied by simulations, which provide a to reduce variation in raw materials and improve quality of the Yan and Qu [10] proposed a batch mixing optimization model below. Suppose that there are t (target) components with methodreference to for improve designing the the batch-to-batch batch mixing quality process. consistency The results of TCM under development. Their methods be the is number briefly of described storage TCMof the and study may have contribute demonstrated to the that increase batch in mixing consistency is a valuable of the becontrolled stored. Alsocontents let x in=( xthe, x mixture., …, x ) be Let the amounts of each stored 1 2 s Component-to-Component Interactions: Unlike most tanks, i.e., the maximum number of ubatches=(u , u ,of ···, extracts u ), the amountsthat can efficacy of TCM. 1 2 s Western medicines, TCM often consists of a number of a =(a , a , …, a k 1k 2k tk components whose pharmacological activities may or may not batchcontents of extract of the used constituents for mixing in and the kth of each batch of extract stored. Define )’, the be quantitatively characterized. Besides, the relative proportions batch of extract stored. (ratios) of the components for achieving optimal therapeutic effect are also unknown in addition to possible component-to- methodsFor unidentified can be used. constituents, Thus, we test have values A=(a such, a , …, as a peak), a t×s areas on 1 2 s component (drug-to-drug) interaction among these components. thatthe chromatographicconsists of the contents fingerprint of the obtained components by certain in the batches analytical of Thus, the study of determining the relative ratios of components b matrix for achieving optimal therapeutic effect has become the key to each batch and (L , U i i the success of the TCM development. To study the main effects extractslimits of thestored. ith Now, let be the amount of mixture needed in ) be the minimum and maximum content and interactions of these components, some commonly employed s component.x2 Yan and Qu [10] proposed to maximize ∑i=1 i (1) designsA full are factorial briefly designdescribed is a below. design that consists of all possible different combinations of one level from each factor. If there are max , l vels for the kth factor X , the corresponding full factorial design each batch. Therefore, the optimization model in this study is to k k which maximizes the sum of squares of the used amounts of is called a general l1 l2 ...lK li = 2 (or 3) for all i, the general factorial design is called a 2K (or K K factorialK design. For example, when maximizes the value of (1) under the following constraints 3 ) factorial design. A 2 (or 3 ) factorial design denotes a full x= b, (2) ∑i=1 i factorial design at two levels (or at three levels). In practice, a

Table 5: A Full 24 the follow-up process. The contents of the constituents in the where (2) determines the amount of mixture needed for Factorial Design.Design matrix

Run X1 X2 X3 X4 Y mixture are assumed to be the weighted average of the contents 1 - - - - Y in the extracts, where the weights are the amounts of each batch 1 2 + - - - Y used for mixing;A x' 2  3 - + - - Y L ≤ ≤ U (3) 3 b , 4 + + - - Y4 min ' max ' - - + - Y U U1 U2 Ut L=(minL , 6 + - + - Y5 1 5 6 minwhere, …, min max ),=(max the minimum, max content, …, max limits), the for maximum the constituents content L2 Lt 7 - + + - Y limits for the components in the mixtures and min 7 8 + + + - Y their limits, and, 8 in the mixtures. (3) Ensures that the contents are in the range of 9 - - - + Y9 0≤x ' ≤ u ' (4) , 10 + - - + Y10

11 - + - + Y11

12 + + - + Y12 where (4) is the maximum amount of each batch that can be solved by quadratic programming (QP) algorithm. In TCM 13 - - + + Y be used for mixing. Note that the above optimization model can 13 14 + - + + Y obtained from previous processes like decoction, concentration, 14 manufacturing, batch mixing can be conducted with the extracts - + + + Y 16 + + + + Y15 15 16 and purification. The extracts created are first stored in the storage tanks. Batch mixing ratios are calculated according to the Ann Biom Biostat 2(1): 1012 (2015) 8/4 Chow et al. (2015) Email: Central

Table 7: n = 1. Run X X X Central Composite Design1 for K = 3 and2 3 typicalfactorial 2 4design factorial is design,expressed the inarrangement terms of a numberof the arrays of arrays is given (or runs) that indicate the levels of each factor. For example, for a 1 -1 -1 -1 2 1 -1 -1 (+)in the signs, following the second standard column order of (see successive Table 5). pairs The of first (-) andcolumn (+) 3 -1 1 -1 signs,of the the design third matrix column consists of four (-) of signs successive followed minus by four (-) and(+ signs, plus 4 1 1 -1 th K-1 and so on. In general, the th k column consists of 2 -1 -1 1 followed by 2K-1 (+) signs. In this 24 factorial design, there are 6 1 -1 1 four factors at two levels, with a total of N = 24 = 16 runs.(−) signs The 5 two levels of each factor are conventionally denoted by (-) and 7 -1 1 1 (+) (they are sometimes denoted by 1 and -1). If a variable is 8 1 1 1 continuous, the two levels, (-) and (+), denoted the high and low 9 0 0 0 levels. If a variable is qualitative, the two levels may denote two 10 0 0 different types or the presence and absence of the variable. Each row represents a different combination of one level from each 11 α 0 0 factor. A full factorial design provides estimates not only for main 12 -α0 0 13 0 α 0 main effects and interaction effects can easily be obtained using effects but also for interactions with maximum precision. The 14 0 -α0 Myers, 1976; Hicks, 1982 [11,12]). 0 0 α a table of contrast coefficients and/or Yate’s algorithm (see, e.g., 15 -α Fractional factorial design: A fractional factorial design is Central composite design: A central composite design is a a design that consists of s fraction of a full factorial full factorial design or a fractional factorial design augmented by P a ±a level at each of the factors and central points. The central (½) fraction of a 2K factorial design is called a K n experiment. composite design consists of one center point, eight points on the K-P 2 fractional factorial design. , a When =1, a full factorial design 3 For example, a P cube (a 2 4 reduces to a one-half factorial design. For a full 2 factorial design, noted that a central composite design with K = 2, a = 1, and n = 1 there are 16 effects, including grand average, four main effects, reduces to factorial a 32 factorial arrangement), design (see and Table six 7).star For points. a full It 2 shouldK factorial be design, although the design provides independent estimates for 4 single four-factor interaction. The full 2 factorial design contains the 2K six two-factor interactions, four three-factor interactions, and a 16 observations, which provide independent estimates for each of error unless some runs are repeated. Unlike the full 2K factorial these 16 effects. However, if we consider only a one-half fraction design, - the1 effects, central it compositedoes not give design an estimate provides of an the estimate experimental of the (i.e., only eight observations available), due to limited resources available, it is impossible to obtain 16 independent estimates. For based on n observations at the central point. a 24-1 fractional factorial design, the eight observations cannot experimental error. The experimental error is usually estimated provide independent estimates for the 16 effects alone but Remarks: In addition to the factorial design, the fractional for some confounding effects, such as the sum of a main effect factorial design, and the central composite design, other designs and a three-factor interaction that are confounded with each such as the classical Plackett and Burman design [13] and the other. In practice, however, the three-factor or higher-factor factorial or fractional factorial in randomized block design are interactions are usually negligible (see Table 6). In this case, a also useful. fractional factorial design is useful in estimating the main effects. Animal Studies In practice, a fractional factorial design is useful when there are many factors to be studied because it is almost impossible to As indicated earlier, the use of TCM in treating critical and life- perform a full factorial design even at two levels. threatening diseases has had a long and noble history. It has been actively practiced nowadays in many parts of the world. Since Table 6: A 24-1 TCM often consists of multiple components, it is unquestionable that many components are successful in suppressing different Fractional FactorialDesign Design. matrix types of diseases in humans. However there does not appear to Run X1 X2 X3 X4=X1 X2 X3 Y

1 - - - - Y1 be any evidence (e.g., scientific documentations), which meets 2 + - - + Y2 use in humans. Thus, in the pharmaceutical development, animal studiesstringent such Western as mice, criteria rats, for rabbits, safely dogs, and efficacy, or monkeys to support for testing their 3 - + - + Y3 4 + + - - Y 4 review and approval before they can be used in humans. - - + + Y toxicity and evaluation of efficacy are required for regulatory However, there are tremendous debates regarding whether 6 + - + - Y5 5 6 animal studies are necessary for the development of TCM, 7 - + + - Y 7 especially for those have been used in for thousands of years.

8 + + + + Y8 Most Chinese doctors suggest that it would be better to focus on

Ann Biom Biostat 2(1): 1012 (2015) 9/4 Chow et al. (2015) Email: Central clinical development, instead of going back to animal studies to have been reported, most of them are of poor quality in trials.obtain It evidence is also suggested for a precise that studiespharmacological on mechanisms profile. and It wouldactive methodology including placebo preparation and verification. be better to focus on safety and efficacy by starting with clinical matchingFai et al, [15]placebo also to pointed achieve out the that purpose in many of blinding. clinical trials Ideally, of theChinese characteristics herbal medicines; of the test it drug is very and difficult matching to makeplacebo a qualityshould ingredients should be conducted after safety and efficacy have be identical in color, appearance, smell and taste. The quality For development of Western medicines, animal studies been confirmed. matching placebo should be identical to the test drug in physical form, sensory perception, packaging, and labeling, and it should they enter human trials. This is animal models can provide pharmaceutical(models) are often scientists used the to insight screen how experimental do the drugs drugs work before in the developed a placebo capsule to match a herbal medicine in terms ofhave its nophysical pharmaceutical form, chemical activity. nature, For thisappearance, purpose, packaging Fai et al. [15]and that animal model is predictive of human model. Although there labeling. Based on the assessment results, the developed placebo haveliving beensystem controversial and evaluate debatesthe toxicity over at whichvarious diseased doses assuming animal capsule assessment results suggested that the placebo was found models should be used to screen new drugs before they can proceed to the clinical trials, there are certain animal models a matching placebo could be created for a RCT involving herbal in different therapeutic areas remain good standards for drug satisfactory in these aspects. Thus, Fai et al. [15] concluded that acquire patent for a developed matching placebo. medicine. In addition, Fai et al. [15] also discussed the means to animalscreening models used usedin the in pharmaceutical the pre-clinical industry, test do providefor example, valuable the It should be noted that the preparation of matching placebo informationsubcutaneous, (if they xenografts are predictive in cancer of human drug screening, models), one Although of the concerns is that apparent physiological and genetic differences avoid any possible operational biases that may be introduced due between human and animals, which clearly indicate that the tois extremelythe knowledge important of the to treatment maintain assignment. the integrity The of blindingoral dosage for diseased models are different from the human equivalent. form of capsule is often considered for preparation of matching placebo for clinical trials involving Chinese herbal medicines as it Matching Placebo in Clinical Trials may remove the strong smell and taste of the herbal medicines. In recent years, randomized controlled trials (RCT) have been However, one of the major challenges is that patients or clinicians recognized as the gold standard in clinical trials for evaluation of will reveal the treatment assignments if they break the capsules. Thus, standard operating procedures (SOP) for preventing of the important components in RCTs is blinding. The ultimate patients and clinicians from breaking the capsules are necessary goalsafety of and clinical efficacy trials of is a to test achieve compound a double-blind under investigation. design to avoid One developed. any possible operational biases due to the knowledge of the Calibration of Study Endpoints treatment assignment. Qi et al. [14] conducted a comprehensive review on the validity of matching placebo used in blinded Unlike WMs, the primary study endpoints for assessment clinical trials for Chinese herbal medicine in recent years and of safety and effectiveness of a TCM are usually assessed by a related patents. The review was conducted based on a database quantitative instrument or the four diagnostic procedures by called the Wanfang Database, which contains a total of 827 Chinese journals of medicine and/or pharmacy, from 1999 to instrument has been criticized in many ways. First, it may not captureexperienced the trueChinese health doctors. of status The ofassessment the patients by a with quantitative diseases matching placebo. A total of 77 blinded clinical trials utilizing under study (e.g., by asking wrong questions). Second, it may not 2005 and 598 full-length articles related to clinical trials utilizing detect the effect of the test treatment under investigation. As an itmatching was found placebo that for nearly Chinese half medicine of the clinical were extracted trials did manually not pay from 0 (perfect health) to 100 (worst possible disease status). attentionfrom the 598to the articles. physical After quality reviewing of the testingthe 77 full-lengthdrug and matching articles, example, consider a quantitative instrument with possible scores placebo and whether they were comparable in terms of physical of health status: Health Mild Moderate quality. The rest provided very limited information regarding Supposeand Severe the scores can be classified into the following categories the preparation of matching placebo. Thus, the integrity of (0-25), (26-50),Health) and a patient (51-75), with a score of 26(76-100). (Mild) despiteIn this case, they there only differis significant by one difference point. On thebetween other a hand, patient a patientwith a scorewith ofa score 25 ( of 26 and a patient with betweenblinding isthe questionable. test drug and Among the matching the 598 articles,placebo. unfortunately,Based on this Mild disease status review,only 2 articles Qi et al. (2.6%) [14] concludedspecifically that validated researchers the comparability in Chinese although they differ by 24 points. Thus, the assessment based medicine commonly ignored the quality of the matching placebo a score of 50 are both considered having in comparison to the test drug. This may have led to substantial not only subjective, but also lack of validity. Consequently, the bias in clinical trials. As a result, Qi et al. [14] urged that quality reliabilityon a quantitative of the assessment instrument is bya concern, experienced especially Chinese when doctors there is evidence of large rater-to-rater variability. developed and carefully evaluated in order to reduce possible Thus, although the quantitative instrument is developed biasspecifications in randomized and evaluationcontrolled TCM of the trials. matching placebo must be by the community of Chinese doctors and is considered a gold As indicated by Qi et al. [14], only a small number of standard for assessment of safety and effectiveness of the TCM randomized controlled trials in traditional Chinese medicine under investigation, it may not be accepted by the Western

Ann Biom Biostat 2(1): 1012 (2015) 10/4 Chow et al. (2015) Email: Central clinicians not only due to the lack of validity and reliability, For the third question, if the TCM is intended for use of but also the interpretation of the assessment (or translation of Chinese doctors but it is conducted by Western clinicians, assessment to well-established and widely accepted clinical difference in perception regarding how to prescribe the TCM is of great concern. The preparation of a package insert based on to conceptually understand the clinical meaning of the difference the clinical data could be a major issue, not only to the sponsor detectedendpoints). by Inthe practice, subjective it is Chinese very difficult quantitative for a Western instrument clinician due but also to regulatory authorities. Similar comments apply to the to fundamental differences in medical theory, perception and situation where the TCM is intended for use of Western clinicians, practice. but the trial is conducted by Chinese doctors. Thus, for modernization or Westernization of TCMs, whether As a result, it is suggested that the intention of use (i.e., the subjective quantitative instrument can accurately and reliably labeling for the indication) be clearly evaluated when planning a assess the safety and effectiveness of the TCM is a concern for TCM clinical trial. In other words, the sponsor needs to determine development of TCM. In practice, it is then suggested that a clinical trial be conducted to calibrate the subjective quantitative Chinese doctors only, or both Western clinicians and Chinese assessment against either life events or well-established clinical doctorswhether atthe the TCM planning is intended stage for ofuse a of TCM Western clinical clinicians’ trial, for only, an endpoints that are commonly used in assessment of Western adequate package insert of the target diseases under study. medicines. The clinical trials should consist of two arms: one arm will include subjects with diseases under study diagnosed Transition from Experience-Base to Evidence-Base by the subjective quantitative instrument and the other arm Clinical Practice will include subjects diagnosed by Western diagnostic or testing As indicated earlier, TCMs have been in practice for thousands procedures. Each subject post-treatment will be assessed by both of years. Many of the commonly used TCMs were found safe and Chinese doctors using the quantitative instrument and Western clinicians based on the well-established and widely accepted study endpoints [16]. efficacious. However, evidence of safety and efficacy of these TCM Package Insert were not documented for scientific evaluation. Unlike evidence- based clinical data, the experience-based clinical information has For the research and development of a TCM, before a TCM been criticized for lacking of scientific validity and reliability for clinical trial is conducted, the following questions are commonly areassessment likely to of report safety only and successfulefficacy of cases,the TCMs while (currently those patients being asked. whoused fail or under (which development). may be due to As severe an example, adverse Chinese events patients or lack (1) Will the TCM clinical trial be conducted by Chinese doctors alone, Western clinicians alone, Western clinicians who have some background of Chinese herbal medicine alone, or both consideredof efficacy) not are only likely subjective, seeking forbut alternativesalso biased (due and thento selection lost to Chinese doctors and Western clinicians? bias)follow-up. and misleading. As a result, experience-based clinical information is (2) Will traditional Chinese diagnostic and/or trial In practice, how to collect relevant and important clinical procedures be used throughout the TCM clinical trial? interest to clinical scientists for development of TCMs. Most (3) Upon approval, is the TCM intended for use by Chinese Chinesedata from doctors experience-based resist to (i) collectclinical clinical practice data is then that ofthey particular are not doctors or Western clinicians? familiar with, and (ii) cooperate with Western doctors to collect further information from their patients due to fundamental trial is to be conducted by Chinese doctors alone, the following differences in culture and clinical theory, perception, and practice. questionsWith respect arise. First, to the should first the two Chinese questions, diagnostic if the procedure TCM clinical be validated in order to provide an accurate and reliable assessment evidence-based clinical practice requires careful communication of the TCM? In addition, it is of interest to determine how an andThus, planning. the transition This from transition experience-based is essential clinical for achieving practice the to observed difference obtained from the Chinese diagnostic ultimate goal of modernization and/or Westernization of TCMs. procedure can be translated to the clinical endpoint commonly used in similar WM clinical trials with the same indication. These CONCLUDING REMARKS two questions can be addressed statistically by the calibration One of the key issues in botanical drug product or TCM and validation of the Chinese diagnostic procedure with respect development is to clarify the difference between Westernization to some well-established clinical endpoints for evaluation of of TCM and modernization of TCM. For Westernization of Western medicines. If the TCM clinical trial is to be conducted TCM, we follow regulatory requirements at critical stages of by Western clinicians or Western clinicians who have some the process for pharmaceutical development including drug background of Chinese herbal medicine, the standards and discovery, formulation, laboratory development, animal studies, consistency of clinical results as compared to those WM clinical clinical development, manufacturing process validation and trials are ensured. However, the good characteristics of TCM may quality control, regulatory submission, review, and process be lost during the process of the conduct of the TCM clinical trials. despite the fundamental differences between WM and TCM. On the other hand, if the TCM clinical trial is to be conducted For modernization of TCM, it is suggested that regulatory by both Chinese doctors and Western clinicians, difference in medical practice and/or possible disagreement regarding the fundamental differences between WM and TCM. In other words, diagnosis, treatment, and evaluation are major concerns. requirements should be modified in order to account for the

Ann Biom Biostat 2(1): 1012 (2015) 11/4 Chow et al. (2015) Email: Central we still ought to be able to see if TCM is really working with

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Cite this article Chow SC, Pong A (2015) Scientific Issues in Botanical Drug Product Development. Ann Biom Biostat 2(1): 1012.

Ann Biom Biostat 2(1): 1012 (2015) 12/4