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WORLD SCIENCE AND TECHNOLOGYMODERNIZATION OF TRADITIONAL CHINESE MEDICINE AND MATERIA MEDICAVolume 14, Issue 4, August 2012Online English edition of the Chinese language journal

Received date: 3 August 2012*Corresponding author. Tel.: +86-10-64014411-2411; E-mail: leiy999@163.com Foundation item: Supported by the National Major Novel Drug Innovation and Development of the Ministry of Science and Technology of China (2009ZX09301-005). Copyright © 2012, World Science and Technology Press. Published by Elsevier B.V. All rights reserved.

Cite this article as: Mode Tradit Chin Med Mater Med, 2012, 14(4): 1831–1834

Optimization Mode of Innovative Chinese Medi-cine Formulations Based on Traditional Chinese Medicine Hospital Preparations

Tian Yuanxiang1, Lei Yan2*, Cao Hongxin2*, Weng Weiliang3

1 Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China 2 China Academy of Chinese Medical Sciences, Beijing 100700, China 3 Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China

Abstract: This study was aimed at investigating the optimization model of innovative Chinese medicine formulations based on traditional Chinese medicine (TCM) hospital preparations. A literature review was conducted to analyze the importance and characteristics of TCM hospital preparations. Then, the optimization process and methods of hospital preparations were summarized and explored. The resultsshowed that hospital preparation is an important and fundamental resource of new drug development, with characteristics of abundant clin-ical experience, multiple formulations, multiple dosage forms, well-established efficacy and reliable safety. Hospital preparations may pro-vide a rich material foundation for the screening of new drug development, which can shorten the development cycle and reduce research cost. However, there is still a gap between hospital preparations and innovative drugs. Based on our optimization work experiences, the optimization of hospital preparations should comply with the general principles and process of optimizing innovative Chinese medicine formulations, which can be divided into three parts, i.e., optimization of component formulation, optimization of clinical trial protocols and assessment before and after clinical trials. The optimization process should be well focused, so as to facilitate comprehensive optimization. Before optimization, the investigational prescription should undergo qualitative and quantitative evaluation for the first time. Based on the sponsor’s final revision, the second qualitative and quantitative evaluation should be performed before the initiation of clinical trials. After clinical trials, the prescription should undergo qualitative and quantitative evaluation for the third time according to the findings of clinical trials. It was concluded that it is possible to provide an optimization model of innovative Chinese medicine formulations based on TCM hospital preparations.

Key Words: Formulation, new drug, traditional Chinese medicine, clinical, hospital preparation, optimization, mode

1 Developing a concept of optimization and its mode of innovative Chinese medicine formula-tions

In order to establish an independent new drug development system and promote the strategic transformation of pharma-ceutical industry development in China, we consider that in- novative Chinese medicine is of good originality, which should be regarded as an advantageous field of new drug research and development (R&D) in China. In recent years, the new drug approval process in China has introduced some new characteristics, including 1) higher re- quirements for efficacy evaluation, involving preclinical ani- mal experiments, application experiences and clinical stu- dies; 2) higher requirements for the analysis of formulation rationality; 3) focusing on the impact of quality control of trials on the evaluability of trial findings, which involves the evaluation of quality control practices of trials; 4) emphasiz-

ing comprehensive evaluation, i.e., an overall assessment in terms of pharmaceutics, pharmacology and toxicology, as well as clinical medicine; 5) focusing more on the advantages of a new drug; and 6) being more cautious and more risk con- scious of sponsors when submitting new drug applications [1]. Several problems, however, are still being identified in the process of new drug R&D. For instance, a new drug does not have sufficiently rigorous formulation of components; the preparation techniques, dosage forms, administration route and site, categories of application and components and their doses are being changed after the completion of relevant trials [2]; or the new drug has unspecified indications, inadequate clinical efficacy or irrational clinical trial protocols [3]. With- out a favorable basis in the early stage of new drug devel-opment, research funds would be wasted to a great extent than at later stages. Zhu Feipeng et al. [1] explored the potential reasons for disapproving innovative Chinese drug application and iden-

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tified the following major problems: irrational formulation, without evidence supported by traditional Chinese medicine (TCM) theories or trial findings; lack of basis in the selection of dosage form and administration route; insufficient basis in the decision of manufacturing techniques; faulty studies of quality standards; the applied indication not supported by non-clinical effectiveness trials; flaws or risks in safety trials; no specific or well-established clinical positioning, indicat-ing that sponsors often define excessively broad clinical in-dications with the thought of “more is better,” but corre-sponding non-clinical pharmacodynamic data is not provided or the provided data lacks relevance to the applied indications; and several defects in terms of trial design, efficacy outcome measures, statistic analysis and selection of positive control, resulting in the difficulty for existing research data to provide supporting evidence for the efficacy of a new drug. Besides, poor quality control of trials is another challenging issue, such as breach of blinding, non-strict compliance with Good Clini- cal Practice (GCP) and ineffective management of the thera-peutic process of subjects. In recent years, an increasing number of innovative Chi-nese drugs are entering the market. However, the problem of “new drug is not new” greatly compromises the social and commercial value of new drugs [3], and their overall clinical efficacy still needs to be further improved. The fundamental reason for this is insufficient or inappropriate preclinical effi- cacy studies of new drugs. Therefore, a research program named “Optimization Plat-form for Innovative Chinese Medicine Formulations” was sponsored by the Ministry of Science and Technology of China in its “Construction of Platforms for Major New Drug Innovation and Development,” a part of the 11th five-year plan of National Major Scientific Projects. This program aims to focus on clinical efficacy as a fundamental factor for the R&D of innovative Chinese medicine, collect the wisdom of relevant experts and emphasize that innovative Chinese medicine formulations should have a favorable clinical re-search basis to strengthen the most basic and essential parts of new drug R&D. Based on our experiences in such optimi- zations, we plan to develop an optimization mode for inno-vative Chinese medicine formulations and to build a platform for major R&D programs of innovative Chinese medicines.

2 Optimization of innovative Chinese medicine formulations as an important part of new drug R&D

The approval of innovative Chinese medicines is a con-tinuous process. Once started, even with defects, it would not stop until being forced to terminate. The defects or flaws, especially those related to the evaluation of clinical efficacy, must be identified and resolved before the initiation of the new drug approval process. Drug efficacy varies with formulation composition and

pharmaceutical techniques, and thus we have to start over if the formulation composition or a pharmaceutical technique changes, which means the start of R&D of another new drug. Therefore, optimization of innovative Chinese medicine for- mulations should be a fundamental and critical part of major R&D programs of innovative Chinese medicines. In addition, constant communication with new drug evaluation centers and relevant reviewers during the R&D process before ap-plication is also encouraged [4].

3 Hospital preparation as a main con-tributor to new drug development [5]

Hospital preparation has long been an important and fun-damental resource for new drug development [6]. Currently, at least 90% of the approved and marketed Chinese patented medicines are developed based on hospital preparations [7], such as Sanjiu Weitai, Kelisha, Zhuanggu Guan- jie Pills, Pediatric Longmu Zhuanggu Granules [8] and Jing- yin Granules [9]. Now, many new drugs with annual sales ex-ceeding 100 million yuan RMB are also derived from hos-pital preparations, including Compound Danshen Dripping Pills, Yihua Kernel Oil (Kanglaite injection), Weisu Gran-ules, Xiaoke Pills, Tongxinluo Capsules, etc. [10]. As a re-sult, investigation of optimization modes for hospital pre- parations is prioritized in the optimization of innovative Chinese medicines.

4 Characteristics of hospital preparations

The appearance of hospital preparations is associated with the particular conditions and the history of pharmaceutical evolution in China, which is different from those of Euro-pean and American countries. Validated in clinical practice, hospital preparations have characteristics of multiple for-mulations, multiple dosage forms, well-established efficacy and reliable safety. Thus, hospital preparations may provide a rich material foundation for the screening of new drug de- velopment, which may avoid aimless searching and detours, shorten the development cycle and reduce the research cost [5]. Due to the different requirements for hospital preparations and new drugs there is still a gap between them, and the potential difficulties and challenges in new drug develop-ment must be well recognized. A new drug is mainly based on its formulation composition. After the determination of formulation composition, functions and indications of a new drug, we have to carry out a series of studies according to the registration and application requirements for innovative Chinese medicines issued by the State Food and Drug Ad-ministration of China. During the research process, we should attach great importance to the extraction and preparation techniques; select dosage forms on the basis of medication profiles and clinical usage; and also ensure the controllabil-ity of preparation quality, which may involve the use of both

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specific and representative parameters in the content deter-mination of compounded Chinese medicinal preparations. Stability study of preparations is one of the main parts of drug quality evaluation, which is of great importance in the research, development, registration and management of drugs. Defects or omissions in any part of the research process may lead to inadequacy of the submitted data, thereby a de-lay in the approval process, and mistakes made in some key parts of the research process may even result in a total fail-ure [11].

5 Optimization process based on hospital preparations

Based on our earlier experiences in optimization work, the optimization of hospital preparations should comply with the general principles and procedures of optimizing innovative Chinese medicine formulations, which can be divided into three parts, i.e., optimization of component formulation, op- timization of clinical trial protocols and assessment before and after clinical trials. In the process of determining com-ponent formulation, dosage and proportion of each compo-nent and functions and indications, as well as optimizing the clinical efficacy of a new drug, the accumulation of relevant studies and experiences from prior literature is of great im-portance. And the process can be improved through con-tinuous discussions or consultations with sponsors, industry professionals and multidisciplinary experts. The optimization of clinical trial protocols should be ac-complished with several rounds of revisions after discus-sions with peer experts or repeated consultations with mul-tidisciplinary experts. In the process of such optimization, it is important to collect the wisdom of experts and to streng- then the clinical efficacy. Assessment before or after clinical trials mainly targets optimized contents. Assessment before clinical trials mainly aims to determine if the clinical trials can be initiated, whereas assessment after clinical trials aims to conduct a comprehensive evaluation of the efficacy and safety findings from the clinical trials so as to determine if the new drug application can be warranted.

6 Optimization methods based on hospital preparation

Based on our earlier experiences in optimization work, the optimization of hospital preparations should be well focused, indicating that energy and financial resources should be focused on the optimization of a key part of the formulation in order to facilitate comprehensive optimization. For ex-ample, the product of Jinchai Antivirus Granules is derived from Xiaochaihu Decoction and based on clinical observa-tions the sponsor found that it was effective for both wind- heat cold and wind-cold cold. But the previously established indication only included wind-heat cold, thus the sponsor focused on the optimization of its indication. After discus-

sion and evaluation, experts concluded that since the exist-ing formulation is mainly composed of drugs for wind-heat syndrome, the expansion of its indication is not justified. Based on TCM theories, wind-heat exterior syndrome is opposite to wind-cold exterior syndrome, and coexistence of both is deemed impossible. A formulation cannot deal with both wind-heat and wind-cold exterior syndromes. As a result, the indication cannot be expanded. If a for-mulation can address both wind-heat and wind-cold syn-dromes, then it targets semi-exterior and semi-interior syn-dromes or interior syndrome rather than any exterior syn-drome. In the process of optimization, the discussion of com- ponent formulation, sources and other factors has also streng- thened the sponsor’s understanding of the formulation. A general process for the optimization of innovative Chinese medicine formulations is developed as follows: First, it should be determined which part of the formulation needs to be optimized; second, based on the category of the formulation relevant experts should be invited to attend an onsite optimization conference, which may include an ex-planation of the optimization background and purpose of the formulation by the sponsor, expert appraisals, the sponsor’s replies to questions raised by experts or in discussions with experts, and a summary of expert opinions; third, based on the conference summary complied after a conference the sponsor should carefully consider the expert opinions to make a decision; and finally, the action taken by the sponsor should be followed out. Specifically, experts present at the conference may fill out or score several forms like “Opinionnaire on the optimization of innovative Chinese medicine formulations” and “Plat-forms for the optimization of innovative Chinese medicine formulations—quantitative parameters for comprehensive evaluation.” Based on the feedbacks of experts, the investi-gational formulation should undergo qualitative and quanti-tative evaluation for the first time (before optimization). Next, based on the sponsor’s final revision of the formu-lation, the second qualitative and quantitative evaluation should be performed (before the initiation of clinical trials) to determine whether clinical trials could be initiated or not. Subsequently, the formulation should undergo qualitative and quantitative evaluation for the third time according to the findings of clinical trials (after the trials) to determine if the new drug application can be warranted and to also de-fine the role of the formulation relative to other comparable new drug formulations. Finally, the chance of getting ap-proval for and the market prospect of the new drug could be preliminarily estimated or predicted.

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