On Traditional Chinese Medicine Clinical Trials

On Traditional Chinese Medicine Clinical Trials

Chow, Shein-Chung

In recent years, the Westernization of traditional Chinese medicine (TCM) has attracted much attention in pharmaceutical research and development. One of the key issues in Westernization of TCM is how to conduct a scientifically valid clinical trial to evaluate safety and effectiveness of the TCM under investigation. A typical approach is to conduct a clinical trial the Western way by ignoring the fact that there are fundamental differences between a TCM and a Western medicine intended for the same indication. These fundamental differences include (1) medical theory/mechanism and practice (ie, the concept of global dynamic balance/harmony among organs of the body versus local site of action); (2) techniques for diagnosis (ie, subjective diagnosis of inspection, auscultation and olfaction, interrogation, pulse taking and palpation versus objectively clinical evaluation); and (3) treatment (ie, personalized flexible dose of multiple components versus fixed dose). In this article, some practical issues, including validation of a quantitative instrument, the use of matching placebo, and sample size calculation when conducting a TCM clinical trial are discussed. We also discuss strategy for statistical quality control (QC) for raw materials, inprocess materials or final product in terms of testing for consistency, stability analysis for estimation of drug expiration dating period, and regulatory requirements for future TCM research and development.

Key Words

Global balance/harmony;

Calibration;

Validation;

Test for consistency;

Multiple components;

Flexible dose

INTRODUCTION

In recent years, as more and more innovator drug products are going off patent, the search for new medicines that treat critical or lifethreatening diseases has become the center of attention of many pharmaceutical companies. As indicated by Chow and Liu (1), pharmaceutical research and development is a lengthy and costly process. On average, it may take more than 12 years to bring a promising compound to the market. The probability of success, however, is usually very low. In the past decade, tremendous effort was put on drug research and development, yet only a handful of new drug products were approved by the regulatory agencies. As a result, an alternative approach for drug discovery is necessary. This leads to the study of the potential use of promising traditional Chinese medicines (TCMs), especially for those intended for treating critical or life-threatening diseases. A TCM is defined as a Chinese herbal medicine developed for treating patients with certain diseases as diagnosed by the four Chinese major techniques of inspection, auscultation and olfaction, interrogation, and pulse taking and palpation based on the traditional Chinese medical theory of global dynamic balance among the functions/activities of all organs of the body.

Unlike evidence-based clinical research and development of a Western medicine (WM), clinical research and development of a TCM is usually experience based, with anticipated variability due to subjective evaluation of the disease under study. The use of TCM in humans for treating various diseases has a history of more than 5,000 years, although no scientific documentation is available regarding clinical evidence of safety and efficacy of these TCMs.

In the past several decades, regulatory agencies of both China and Taiwan have debated which direction the TCM should take-Westernization or modernization. The Westernization of TCM is referred to the adoption of the typical (Western) process of pharmaceutical research and development for scientific evaluation of the safety and effectiveness of the TCM products under investigation, while the modernization of TCM is to evaluate the safety and effectiveness of TCM the Chinese way (ie, different sets of regulatory requirements and evaluation criteria) scientifically. Although both China and Taiwan do attempt to build up an environment for the modernization of TCM, they seem to adopt the Westernization approach. As a resuit, in this article we place our emphasis on the Westernization of TCM.

In practice, it is a concern whether a TCM can be scientifically evaluated the Western way due to some fundamental differences between a WM and a TCM. These include differences in formulation, medical practice, drug administration, diagnostic procedure and criteria for evaluation, and flexibility. Under these differences, it is then of interest to the investigators regarding how to conduct a scientifically valid (ie, an adequate and well-controlled) clinical trial for evaluation of the clinical safety and efficacy of the TCM under investigation. In addition, it is also of particular interest to the investigators regarding how to translate an observed significant difference detected by the Chinese diagnostic procedure to a clinically meaningful difference based on some well-established clinical study end point. The purpose of this article is to provide some basic considerations regarding practical issues that are commonly encountered when conducting a TCM clinical trial the Western way.

In the next section, some fundamental differences between a WM and a TCM, which have an impact on the Westernization of TCM, are described. These fundamental differences include the concept of global dynamic balance/harmony among organs of the body (TCM) versus local site action (WM); subjective diagnostic techniques of inspection, auscultation and olfaction, interrogation, pulse taking and palpation (TCM) versus objectively clinical evaluation (WM); and personalized flexible dose with multiple components (TCM) versus fixed dose of single active ingredient (WM). The third section provides some basic considerations of TCM clinical trials. These basic considerations include study design, validation of a quantitative instrument developed for the four major TCM diagnostic techniques, the use/preparation of matching placebo, and sample size calculation. Some practical issues that are commonly encountered when conducting a TCM clinical trail are given next, such as test for consistency in statistical QC of raw material or final product, stability analysis, animal studies, regulatory requirements, and indication, label, and packaging insert. Some concluding remarks, including future strategy and recommendations in TCM research and development, are given in the last section.

FUNDAMENTAL DIFFERENCES

As indicated, the process for pharmaceutical research and development of WMs is well established, and yet it is a lengthy and costly process. This lengthy and costly process is necessary to ensure the efficacy, safety, quality, stability, and reproducibility of the drug product under investigation. For pharmaceutical research and development of a TCM, one may consider directly applying this well-established process to the TCM under investigation. However, this process may not be feasible due to some fundamental differences between a TCM and a WM. Some fundamental differences between a WM and a TCM are summarized in Table 1. These fundamental differences are briefly described next.

MEDICAL THEORY/MECHANISM AND PRACTICE

Medical Theory and Mechanism. TCM is a 3000-year-old holistic medical system encircling the entire scope of human experience. It combines the use of Chinese herbal medicines, acupuncture, massage, and therapeutic exercise such as Qigong (the practice of internal air) and Taigie for both treatment and prevention of disease. With its unique theories of etiology, diagnostic systems, and abundant historical literature, TCM itself consists of Chinese culture and philosophy, clinical practice experience, and the use of many medical herbs.

Chinese doctors believe how a TCM functions in the body is based on the eight principles, five-element theory, five Zang and six Fu, and information regarding channels and collaterals. Eight principles consist of Yin and Yang (ie, negative and positive), cold and hot, external and internal, and Shi and Xu (ie, weak and strong). The eight principles help Chinese doctors differentiate syndrome patterns. For instance, people with Yin will develop disease in a negative, passive, and cool way (eg, diarrhea and back pain), while people with Yang will develop disease in an aggressive, active, progressive, and warm way (eg, dry eyes, tinnitus, and night sweats). The five elements (earth, metal, water, wood, and fire) correspond to particular organs in the human body. Each element operates in harmony with the others.

The five Zang (or Yin organs) include heart (including the pericardium), lung, spleen, liver, and kidney, while the six Fu (or Yang organs) include gall bladder, stomach, large intestine, small intestine, urinary bladder, and three cavities (ie, chest, epiastrium, and hypogastrium). Zang organs can manufacture and store fundamental substances. These substances are then transformed and transported by Fu organs. TCM treatments involve a thorough understanding of the clinical manifestations of Zang-Fu organ imbalance and knowledge of appropriate acupuncture points and herbal therapy to rebalance or maintain the balance of the organs. The channels and collaterals are the representation of the organs of the body. They are responsible for conducting the flow of energy and blood through the entire body.

The elements of TCM can also help to describe the etiology of disease, including six exogenous factors (ie, wind, cold, summer, dampness, dryness, and fire); seven emotional factors (ie, anger, joy, worry, grief, anxiety, fear, and fright); and other pathogenic factors. Once all of the information is collected and processed into a logical and workable diagnosis, the traditional Chinese medical doctor can determine the treatment approach.

Under the medical theory and mechanism described above, Chinese doctors believe that all of the organs within a healthy subject should reach the so-called global dynamic balance or harmony among organs. Once the global balance is broken at certain sites such as heart, liver, or kidney, some signs and symptoms then appear to reflect the imbalance at these sites. An experienced Chinese doctor usually assesses the causes of global imbalance before a TCM with flexible doses is prescribed to fix the problem. This approach is sometimes referred to as a personalized (or individualized) medicine approach.

Medical Practice. Different medical perceptions regarding signs and symptoms of certain diseases could lead to a different diagnosis and treatment for the diseases under study. For example, the signs and symptoms of type 2 diabetic subjects could be classified as the disease of thirsty reduction by Chinese doctors. The disease of type 2 diabetes is not recognized by Chinese medical literature, although it has the same signs and symptoms as the well-known disease of thirsty reduction. This difference in medical perception and practice has an impact on the diagnosis and treatment of the disease.

In addition, we tend to see the therapeutic effect of WMs sooner than TCMs. TCMs are often considered for patients who have chronic diseases or non-life-threatening diseases. For critical or life-threatening diseases such as cancer or stroke, TCMs are often used as the secondline or third-line treatment with no other alternative treatments. In many cases, such as patients with a later phase of cancer, TCMs are often used in conjunction with WMs without the knowledge of the primary care physicians.

TECHNIQUES OF DIAGNOSIS

The Chinese diagnostic procedure for patients with certain diseases consists of four major techniques: inspection, auscultation and olfaction, interrogation, and pulse taking and palpation. All these diagnostic techniques aim mainly at providing an objective basis for differentiation of syndromes by collecting symptoms and signs from the patient. Inspection involves observing the patient’s general appearance (strong or weak, fat or thin); mind; complexion (skin color); five sense organs (eye, ear, nose, lip, and tongue); secretions; and excretions. Auscultation involves listening to the voice, expression, respiration, vomit, and cough. Olfaction involves smelling the breath and body odor. Interrogation involves asking questions about specific symptoms and the general condition, including history of the present disease, past history, personal life history, and family history. Pulse taking and palpation can help to judge the location and nature of a disease according to the changes of the pulse.

The Chinese diagnostic procedure of inspection, auscultation and olfaction, interrogation, and pulse taking and palpation is subjective, with large between-rater variability (ie, variability from one Chinese doctor to another). This subjectivity and variability will have an impact not only on the patient’s evaluability but also on the prescribability of TCM, discussed further next.

Objective Versus Subjective Criteria for Evaluability. For evaluation of a WM, objective criteria based on some well-established clinical study end points are usually considered. For example, response rate (ie, complete response plus partial response based on tumor size) is considered a valid clinical end point for evaluating clinical efficacy of oncology drug products. Unlike WMs, the Chinese diagnostic procedure for evaluation of a TCM is very subjective. The use of a subjective Chinese diagnostic procedure has raised the following issues. First, it is a concern whether the subjective Chinese diagnostic procedure can accurately and reliably evaluate clinical efficacy and safety of the TCM under investigation. Thus, it is suggested that the subjective Chinese diagnostic procedure should be validated in terms of its accuracy, precision, and ruggedness before it can be used in TCM clinical trials. A validated Chinese diagnostic procedure should be able to detect a clinically significant difference if the difference truly exists. On the other hand, it is not desirable to wrongly detect a difference when there is no difference.

In clinical trials, evaluation is usually based on some validated tools (instruments), such as laboratory tests. Test results are then evaluated against some normal ranges for abnormality. Thus, it is suggested that the Chinese diagnostic procedure must be validated in terms of validity and reliability and its false-positive and falsenegative rates before it can be used for evaluation of clinical efficacy and safety of the TCM under investigation.

TREATMENT

TCM prescriptions typically consist of a combination of several components. The combination is usually determined based on the medical theory of global dynamic balance (or harmony) among organs and the observations from the Chinese diagnostic procedure. The use of the Chinese diagnostic procedure is to find out what caused the imbalance among these organs. The treatment is to reinstall the balance among these organs. Thus, the dose and treatment duration are flexible in order to achieve the balance. This concept leads to the concept of socalled personalized (or individualized) medicine, which minimizes intrasubject variability.

Single Active Ingredient Versus Multiple Components. Most WMs contain a single active ingredient. After drug discovery, an appropriate formulation (or dosage form) is necessarily developed so that the drug can be delivered to the site action in an efficient way. At the same time, an assay is necessarily developed to quantitate the potency of the drug. The drug is then tested on animals for toxicity and humans (healthy volunteers) for pharmacological activities. Unlike the WMs, TCMs usually consist of multiple components with certain relative proportions among the components. As a result, the typical approach for evaluation of single active ingredient for WM is not applicable.

In practice, one may suggest evaluating the TCM component by component. However, this is not feasible due to the following difficulties. First, in practice, analytical methods for quantitation of individual components are often not tractable. Thus, the pharmacological activities of these components are not known. It should be noted that the component that comprises the major proportion of the TCM may not be the most active component. On the other hand, the component that has the least proportion of the TCM may be the most active component of the TCM. In practice, it is not known which relative proportions among these components can lead to the optimal therapeutic effect of the TCM. In addition, the relative component-tocomponent or component-by-food interactions are usually unknown, which may have an impact on the evaluation of clinical efficacy and safety of the TCM.

Fixed Dose Versus Flexible Dose. Most WMs are usually administered in a fixed dose (say 10-mg tablets or capsule). On the other hand, since a TCM consists of multiple components with possible varied relative proportions among the components, a Chinese doctor usually prescribes the TCM with different relative proportions of the multiple components based on the signs and symptoms of the patient according to his or her best judgment following a subjective evaluation based on the Chinese diagnostic procedure. Thus, unlike a WM prescribed as a fixed dose, a TCM is often prescribed as an individualized flexible dose.

The approach of WM with a fixed dose is a population approach to minimize the betweensubject (or intersubject) variability, while the approach to TCM with an individualized flexible dose is to minimize the variability within each individual. In practice, it is a concern whether an individual flexible dose is compatible with a Western evaluation of the TCM. An individualized flexible dose depends heavily on the Chinese doctor’s subjective judgment, which may vary from one Chinese doctor to another. As a result, although an individualized flexible dose does minimize intrasubject variability, the variability from one Chinese doctor to another (ie, the doctor-to-doctor or rater-to-rater variability) could be huge and hence nonnegligible.

REMARKS

For the research and development of a TCM, before a TCM clinical trial is conducted, the following questions are necessarily asked:

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 Chinese doctors and Western clinicians?

2. Will traditional Chinese diagnostic or trial procedures be used throughout the TCM clinical trial?

3. On approval, is the TCM intended for use by Chinese doctors or Western clinicians?

With respect to the first two questions, if the TCM clinical trial is to be conducted by Chinese doctors alone, the following questions arise: First, should the Chinese diagnostic procedure be validated to provide an accurate and reliable assessment of the TCM? In addition, it is of interest to determine how an observed difference obtained from the Chinese diagnostic procedure can be translated to the clinical end point commonly used in similar WM clinical trials with the same indication. These two questions can be addressed statistically by the calibration and validation of the Chinese diagnostic procedure with respect to some well-established clinical end points for evaluation of Western medicines. If the TCM clinical trial is to be conducted by Western clinicians or Western clinicians who have some background of Chinese herbal medicine, then the standards and consistency of clinical results as compared to those WM clinical trials are ensured. However, the good characteristics of TCM may be lost during the process of the conduct of the TCM clinical trials. On the other hand, if the TCM clinical trial is to be conducted by both Chinese doctors and Western clinicians, difference in medical practice or possible disagreement regarding the diagnosis, treatment, and evaluation are major concerns.

For the third question, if the TCM is intended for use of Chinese doctors but it is conducted by Western clinicians, difference in perception regarding how to prescribe the TCM is of great concern. The preparation of a package insert based on the clinical data could be a major issue not only to the sponsor but also to regulatory authorities. Similar comments apply when the TCM is intended for use of Western clinicians, but the trial is conducted by Chinese doctors.

As a result, it is suggested that the intention of use (ie, labeling for the indication) be clearly evaluated when planning a TCM clinical trial. In other words, the sponsor needs to determine whether the TCM is intended for use of Western clinicians only, Chinese doctors only, or both Western clinicians and Chinese doctors at the planning stage of a TCM clinical trial, for an adequate package insert of the target diseases under study.

BASIC CONSIDERATIONS OFTCM CLINICALTRIALS

In this section, we describe some basic considerations that are necessary to ensure the success of a TCM clinical trial.

STUDY DESIGN

To demonstrate clinical efficacy and safety of a TCM under investigation, like WMs, it is suggested that a randomized parallel-group, placebo-controlled clinical trial be conducted. However, it may not be ethical if the disease under study is critical or life-threatening provided that a WM is available. Alternatively, a randomized placebo-control crossover clinical trial or a parallel-group design consisting of three arms (ie, the TCM under study, a WM as an active control, and a placebo) is recommended. The three-arm, parallel-group design allows the establishment of noninferiority/equivalence of the TCM as compared to the active control (WM) and the demonstration of the superiority of the TCM with respect to the placebo.

One of the advantages of a crossover clinical trial is that a comparison within each individual can be made, although it will take a longer time to complete the study. Although a crossover design requires a smaller sample size as compared to a parallel-group design, there are some limitations for the use of crossover design. First, baselines prior to dosing may not be the same. second, when a significant sequence effect is observed, we would not be able to isolate the effects of period effect, carryover effects, and subject-by-treatment effect, which are confounded to one another.

In many cases, factorial designs are used to evaluate the impact of specific components (with respect to the therapeutic effect) by fixing some of the components. For example, we may consider a parallel-group design comparing two treatment groups (one group is treated with the TCM with a specific component, and the other group is treated with the TCM without the specific component). The design of this kind may be useful to identify the most active component of the TCM with respect to the dis eases under study. However, it does not address the possible drug-to-drug interactions among the components.

VALIDATION OF QUANTITATIVE INSTRUMENT

In TCM medical practice, a Chinese doctor usually collects information from the patient with a certain disease through the four subjective approaches as described in the previous section. The purpose of these subjective approaches is to collect information on various aspects of the disease under study, such as signs, symptoms, patient’s performance, and functional activities, so a quantitative instrument with a large number of questions/items is necessary and helpful. For a simple analysis and an easy interpretation, these questions are usually grouped to form subscales, composite scores (domains), or overall score. The items (or subscales) in each subscale (or composite score) are correlated. As a result, the structure of responses to a quantitative instrument is multidimensional, complex, and correlated. As mentioned, a standardized quantitative tool (instrument) is necessary to reduce variability from one Chinese doctor to another (prior to the conduct of a clinical trial).

Guilford (2) discussed several methods, such as Cronbach α for measuring the reliability of internal consistency of a quantitative instrument. Guyatt et al. (3) indicated that a quantitative instrument should be validated in terms of its validity, reproducibility, and responsiveness. Hollenberg et al. (4) discussed several methods for validation of a quantitative instrument, such as consensual validation, construct validation, and criterion-related validation. There is, however, no gold standard regarding how a quantitative instrument should be validated. In this article, we focus on the validation of a quantitative instrument in terms of validity, reliability (or reproducibility), and responsiveness (see, eg, Refs. 5 and 6). As indicated in Chow and Shao (7), the validity of a quantitative instrument is the extent to which the instrument measures what is designed to measure. It is a measure of biasedness of the instrument. The biasedness of a quantitative instrument reflects the accuracy of the instrument. The reliability of a quantitative instrument measures the variability of the instrument, which directly relates to the precision of the instrument. On the other hand, the responsiveness of a quantitative instrument is usually referred to as the ability of the instrument to detect a difference of clinical significance within a treatment.

Hsiao et al. (8) considered a specific design for calibration/validation of the Chinese diagnostic procedure. In the proposed study design, qualified subjects are randomly assigned to receive either a TCM or a WM. Each patient will be evaluated by a Chinese doctor and a Western clinician independently, regardless of which treatment group he or she is in. As a result, there are four groups of data: (1) patients who receive TCM and are evaluated by a Chinese doctor, (2) patients who receive TCM but are evaluated by a Western clinician, (3) patients who receive WM but are evaluated by a Chinese doctor, and (4) patients who receive WM and are evaluated by a Western clinician. Groups 3 and 4 are used to establish a standard curve for calibration between the TCM and the WM. Groups 1 and 2 are then used to validate the Chinese diagnostic procedure based on the established standard curve.

CLINICAL END POINT

Unlike WMs, the primary study end points for assessment of safety and effectiveness of a TCM are usually assessed subjectively by a quantitative instrument by experienced Chinese doctors. Although the quantitative instrument is developed by the community of Chinese doctors and is considered a gold standard for assessment of safety and effectiveness of the TCM under investigation, it may not be accepted by the Western clinicians due to fundamental differences in medical theory, perception, and practice. In practice, it is very difficult for a Western clinician to understand conceptually the clinical meaning of the difference detected by the subjective Chinese quantitative instrument. Consequently, whether the subjective quantitative instrument can accurately and reliably assess the safety and effectiveness of the TCM is always a concern to Western clinicians.

As an example, for assessment of safety and efficacy of a drug product for treatment of ischemic stroke, a commonly considered primary clinical end point is the functional status assessed by the so-called Barthel index. The Barthel index is a weighted functional assessment scoring technique composed of 10 items with a minimum score of O (functional incompetence) and a maximum score of 100 (functional competence). The Barthel index is a weighted scale measuring performance in self-care and mobility, and it is widely accepted in ischemic stroke clinical trials. A patient may be considered a responder if his or her Barthel index is greater than or equal to 60. On the other hand, Chinese doctors usually consider a quantitative instrument developed by the Chinese medical community as the standard diagnostic procedure for assessment of ischemic stroke. The standard quantitative instrument is composed of six domains, which capture different information regarding patient’s performance, functional activities, and signs and symptoms and status of the disease.

In practice, it is of interest to both Western clinicians and Chinese doctors how an observed clinically meaningful difference by the Chinese quantitative instrument can be translated to that of the primary study end point assessed by the Barthel index. To reduce the fundamental differences in medical theory/perception and practice, it is suggested that the subjective Chinese quantitative instrument be calibrated and validated with respect to that of the clinical end point assessed by the Barthel index before it can be used in TCM ischemic stroke clinical trials.

MATCHING PLACEBO

In clinical development, double-blind, placebocontrolled randomized clinical trials are often conducted for evaluation of the safety and effectiveness of a test treatment under investigation. To maintain blindness, a matching placebo should be identical to the active drug in all aspects of size, color, coating, taste, texture, shape, and order except that it contains no active ingredient. In clinical trials, as an advanced technique available for formulation, a matching placebo is not difficult to make because most Western medicines contain a single active ingredient. Unlike Western medicines, TCMs usually consist of a number of components, which often have different tastes. In TCM clinical trials, the TCM under investigation is often encapsulated. However, the test treatment will be easily unblinded if either the patient or Chinese doctor breaks the capsule. As a result, the preparation of a matching placebo in TCM clinical trials plays an important role in the success of the TCM clinical trials.

SAMPLE SIZE CALCULATION

In clinical trials, sample size is usually selected to achieve a desired power for detecting a clinically meaningful difference in one of the primary study end points for the intended indication of the treatment under investigation (see, eg, Ref. 9). As a result, sample size calculation depends on the primary study end point and the clinically meaningful difference that one would like to detect. Different primary study end points may result in very different sample sizes.

For illustration purposes, consider the example concerning a TCM for treatment of ischemic stroke; this TCM was developed with more than 30 years clinical experience with humans. Suppose a sponsor would like to conduct a clinical trial to evaluate scientifically the safety and efficacy of the TCM the Western way as compared to an active control (eg, aspirin). Thus, the intended clinical trial is a doubleblind, parallel-group, placebo-controlled randomized trial. The primary clinical end point is the response rate a patient is considered a responder if his or her functional status assessed by the Barthel index is greater than or equal to 60. Sample size calculation is performed based on the response rate after 4weeks of treatment under the hypothesis of testing for superiority. As a result, a sample size of 150 patients per treatment group is required for achieving an 80% power for establishment of superiority of the TCM over the active control agent. Alternatively, we may consider the quantitative instrument developed by experienced Chinese doctors as the primary study end point for sample size calculation. Based on a pilot study, about 80% (79 of 122) of ischemic stroke patients were diagnosed by one domain of the quantitative instrument. A patient is considered a responder if his or her domain score is greater than or equal to 7. Based on this primary study end point, a sample size of 90 per treatment group is required to achieve an 80% power for establishment of superiority.

The difference in sample size leads to the question of whether the use of the primary end point of response rate based on one domain of the Chinese quantitative instrument could provide substantial evidence of safety and effectiveness of the TCM under investigation.

OTHER ISSUES IN TCM RESEARCH AND DEVELOPMENT

Although TCM has a long history of use in humans, no scientifically valid documentation is available. As indicated by the US Food and Drug Administration (FDA), substantial evidence regarding safety and effectiveness of the test treatment under investigation can only be obtained by conducting adequate and well-controlled clinical trials. However, before the test treatment under investigation can be used in humans, sufficient information regarding chemistry, manufacturing, and control; clinical pharmacology; and toxicology are necessary (see, eg, Ref. 10). Since most TCMs consist of multiple components with unknown pharmacological activities, valid information regarding chemistry, manufacturing, and control; clinical pharmacology; and toxicology are difficult to obtain. These difficulties are briefly described next.

TEST FOR CONSISTENCY

As mentioned, unlike most WMs, TCMs usually consist of a number of components. The pharmacological activities, interactions, and relative proportions of these components are usually unknown. In practice, a TCM is usually prescribed subjectively by an experienced Chinese doctor. As a result, the actual dose received by each individual varies depending on the signs and symptoms as perceived by the Chinese doctor. Although the purpose of this medical practice is to reduce the within-subject (or intrasubject) variability, it could also introduce nonnegligible variability such as variations from component to component and from rater to rater (one Chinese doctor to another). Consequently, reproducibility or consistency of clinical results is questionable. Thus, ensuring the reproducibility or consistency of the observed clinical results has become a great concern to regulatory agencies in the review and approval process. It is also a great concern to the sponsor of the manufacturing process. To address the question of reproducibility or consistency, a valid statistical QC process on the raw materials and final product is suggested.

Tse et al. (11) proposed a statistical QC method to assess a proposed consistency index of raw materials from different resources or final product and may be manufactured at different sites. The consistency index is defined as the probability that the ratio of the characteristics (eg, extract) of the most active component among the multiple components of a TCM from two different sites (locations) is within a limit of consistency. The consistency index close to 1 indicates that the components from the two sites or locations are almost identical. The idea for testing consistency is to construct a 95% confidence interval for the proposed consistency index under a sampling plan. If the constructed 95% confidence lower limit is greater than a prespecified QC lower limit, then we claim that the raw materials or final product has passed the QC and hence can be released for further process or use. Otherwise, the raw materials or final product should be rejected.

ANIMAL STUDIES

The purpose of animal studies is not only to study possible toxicity in animals, but also to suggest an appropriate dose for use in humans, assuming that the established animal model is predictive of the human model. For a newly developed drug product, animal studies are necessary. However, for some well-known TCMs that have been used in humans for years and have a very mild toxicity profile, it is questionable whether animal studies are necessary. It is suggested that all components of TCMs as described in Chinese Pharmacopoeia be classified into several categories depending on their potential toxicities or safety profiles as a basis for regulatory requirements for animal studies. In other words, for some well-known TCM components such as ginseng, animal studies for testing toxicity may be waived depending on past experience of human use, although health risks or side effects following the proper administration of designated therapeutic dosages were not recorded in human use. Note that the German regulatory authority’s herbal watchdog agency, commonly called Commission E, has conducted an intensive assessment of the peer-reviewed literature on some 300 common botanicals with respect to the quality of the clinical evidence and the uses for which the herb can be reasonably considered effective (12).

STABILITY ANALYSIS

Most regulatory agencies require that the expiration dating period (or shelf life) of a drug product must be indicated on the immediate container label before it can be released for use. To fulfill this requirement, stability studies are usually conducted to characterize the degradation of the drug product. For drug products with a single active ingredient, statistical methods for determination of drug shelf life are well established (e.g., 13,14). However, regulatory requirements for estimation of drug shelf life for drug products with multiple components are not available.

Following the concept of estimating shelf life for drug products with a single active ingredient, two approaches are worth considering. First, we may (conservatively) consider the minimum of the shelf lives obtained from each component of the drug product. This approach is conservative and yet may not be feasible due to the fact that (1) not all of the components of a TCM can be accurately and reliably quantitated, and (2) the resultant shelf life may be too short to be useful (see, eg, Ref. 15).

Alternatively, we may consider a two-stage approach for determination of drug shelf life. At the first stage, an attempt should be made to identify the most active components whenever possible. A shelf life can then be obtained based on the method suggested in the FDA and International Conference on Harmonisation guidelines. At the second stage, the obtained shelf life is adjusted based on the relationship or interactions of the most active ingredients and other components. As an alternative, Chow and Shao (16) proposed a statistical method for determining the shelf life of a TCM following a similar idea suggested by the FDA, assuming that the components are linear combinations of some factors.

REGULATORY REQUIREMENTS

Although the use of TCMs in humans has a long history, there have been no regulatory requirements regarding the assessment of safety and effectiveness of the TCMs until recently. For example, regulatory authorities of both China and Taiwan have published guidelines/guidances for clinical development of TCMs (see, eg, Refs. 17-19). In addition, the US FDA also published a guidance for botanical drug products (20). These regulatory requirements for TCM research and development, especially for clinical development, are very similar to well-established guidelines/guidances for pharmaceutical research and development for Western medicines. It is a concern whether these regulatory requirements and the corresponding statistical methods are feasible for research and development of TCM based on the fact that there are so many fundamental differences in medical practice, drug administration, and diagnostic procedure. As a result, it is suggested that current regulatory requirements and the corresponding statistical methods should be modified to reflect these fundamental differences.

It is strongly recommended that regulatory requirements for the development, review, and approval process for Premarin (conjugated estrogen tablets, USP) be consulted because Premarin is a WM consisting of multiple components and is similar to a TCM (21,22). Premarin, which contains multiple components of estrone, equilin, 17a-dihydroequilin, 17a-estradiol, and 173-dihydroequilin, is intended for treatment of moderate-to-severe vasomotor symptoms associated with menopause. The experience with Premarin is helpful in developing appropriate guidelines/guidances for TCM drug products with multiple components.

INDICATION/LABEL

As indicated, it is very important to clarify the intended use of a TCM (by Chinese doctors alone, Western clinicians alone, or both Chinese doctors and Western clinicians) once it is approved by the regulatory agencies. If a TCM is intended for use by Chinese doctors alone, then the clinical trials conducted for obtaining substantial evidence should reflect medical theory of TCM and medical practice of Chinese doctors. The label should provide sufficient information regarding how to prescribe the TCM the Chinese way. On the other hand, if the TCM under investigation is intended for use by Western clinicians alone, patients under study should be evaluated based on clinical study end points for safety and efficacy the Western way. Consequently, the label should provide sufficient information for prescribing the TCM the Western way. If the TCM is intended for both Western clinicians and Chinese doctors, patients are necessarily evaluated by both Western clinical study end points and Chinese diagnostic procedures (eg, some standardized quantitative instrument) provided that the Chinese diagnostic procedure has been calibrated and validated against the well-established Western clinical end point. In this case, there is a clear understanding how an observed difference by Chinese diagnostic procedure can be translated to a clinical effect that is familiar to Western clinicians and vice versa.

CONCLUDING REMARKS

A TCM is defined as a Chinese herbal medicine developed for treating patients with certain diseases as diagnosed by the four major techniques of inspection, auscultation and olfaction, interrogation, and pulse taking and palpation based on traditional Chinese medical theory of global balance among the functions/activities of all organs of the body. When conducting a TCM clinical trial, it is suggested that the fundamental differences between a WM and a TCM, as described in the second section, should be evaluated carefully for a valid and unbiased assessment of the safety and effectiveness of the TCM under investigation.

One of the key issues in TCM research and development is to clarify the difference between Westernization of TCM and modernization of TCM. For Westernization of TCM, we follow regulatory requirements at critical stages of the process for pharmaceutical development, including drug discovery, formulation, laboratory development, animal studies, clinical development, manufacturing process validation and QC, regulatory submission, review, and process despite the fundamental differences between WM and TCM. For modernization of TCM, it is suggested that regulatory requirements should be modified to account for the fundamental differences between WM and TCM. In other words, we still ought to be able to see if TCM is really working with modified regulatory requirements using Western clinical trials as a standard for comparison.

In practice, it is recognized that WMs tend to achieve the therapeutic effect sooner than that of TCMs for critical or life-threatening diseases. TCMs are found to be useful for patients with chronic diseases or non-life-threatening diseases. In many cases, TCMs have shown to be effective in reducing toxicities or improving the safety profile for patients with critical or lifethreatening diseases. As a strategy for TCM research and development, it is suggested that (1) TCM be used in conjunction with a well-established WM as a supplement to improve its safety profile or enhance therapeutic effect whenever possible, and (2) TCM should be considered as the second-line or third-line treatment for patients who fail to respond to the available treatments. However, some sponsors are interested in focusing on the development of TCM as a dietary supplement due to (1) the lack or ambiguity of regulatory requirements, (2) the lack of understanding of the medical theory/mechanism of TCM, (3) the confidentiality of nondisclosure of the multiple components, and (4) the lack of understanding of pharmacological activities of the multiple components of TCM.

Since TCM consists of multiple components that may be manufactured from different sites or locations, the postapproval consistency in quality of the final product is both a challenge to the sponsor and a concern to the regulatory authority. As a result, some postapproval tests, such as tests for content uniformity, weight variation, or dissolution and (manufacturing) process validation, must be performed for quality assurance before the approved TCM can be released for use.

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Shein-Chung Chow

Duke University School of

Medicine, Durham,

North Carolina, USA

Annpey Pong

Eisai Medical Research Inc.,

Ridgefield Park,

New Jersey, USA

Ye-Wil Clung

Carol Electronics Co., Ltd,

Research and

Development Division,

Taichung, Taiwan, ROC

Correspondence Address

Yu-Wei Chang, Carol

Electronics Co., Ltd.,

Research and Development

Division, No. 202, Tung

Kuang Road, Taichung,

Taiwan, ROC (e-mail:

changvick@gmail. com).

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