Guideline ID:[Z] GCL1-1
Medical Rationale for Investigational New Drug Applications of Traditional Chinese Medicine and Natural Drugs
Principles for Literature Review Writing
(Draft 2)
March 18, 2004
Medical Rationale for Clinical Trial Applications of Traditional Chinese Medicine and Natural Drugs
Principles for Writing Literature Reviews
I. Overview
This set of writing guidelines outlines the basic requirements for preparing medical theory and literature documentation when submitting an application for clinical trial registration of traditional Chinese medicines and natural drugs.
New drug research and development for Traditional Chinese Medicine (TCM) and natural drugs differ significantly from those for chemically synthesized drugs. Generally, before conducting pharmaceutical, pharmacological, and clinical trials, these drugs already have a foundation of preclinical research on safety and efficacy, including clinical, pharmacodynamic, and toxicological studies. This foundational evidence is a critical factor influencing the prospects, risks, and technical requirements of drug development and is a key focus during regulatory review. Therefore, carefully reviewing, summarizing, and analyzing existing research data is essential in TCM and natural drug development. It also serves as a primary basis for determining eligibility to proceed to clinical trials. Consequently, it is necessary to establish clear guidelines for writing medical theory sections and compiling literature reviews specific to TCM and natural drugs.
II. Basic Requirements for Writing
The purpose of writing the section on medical theory and literature is to demonstrate the level of support for the safety and efficacy of the drug being developed for its intended indications. This section should reflect the research foundation, objectives, rationale, and methodology. It must highlight the unique characteristics of Traditional Chinese Medicine (TCM), the guiding role of TCM theory, and the supporting evidence from clinical practice experience in TCM. This enables reviewers to evaluate the foundational basis for the drug's safety and efficacy and determine the extent to which it supports progression to clinical trials, thereby establishing appropriate technical requirements.
III. Specific Content Writing Requirements
According to Appendix 1 of the "Drug Registration Management Measures" ("Classification and Technical Requirements for Registration Application Materials of Traditional Chinese Medicine and Natural Drugs"), this section covers the "Purpose and Rationale" of registration application materials 3. It includes an overview of the prescription source and rationale, a summary of traditional TCM theory, ancient literature, current domestic and international research status, or production and usage data, as well as an analysis of the product's innovation and feasibility, including comparisons with existing national standard equivalents.
(1) Prescription Composition, Functions, and Indications
This section specifies the prescription composition, dosage (daily amount), functions, indications, and proposed usage instructions for this project. For traditional Chinese medicine preparations, determine appropriate functions and indications based on the formula's characteristics and TCM theory, using TCM terminology. For natural medicine preparations, define functions and indications based on modern pharmacological research findings.
Proposed indications should appropriately specify Western and Chinese medical diagnoses, disease severity, stages, subtypes, and TCM syndromes.
(II) Purpose of the Study
The study objective must clearly state the purpose of developing this product, with specific and precise justification. The proposed indications or target population should reflect clinical reality and ensure feasibility in new drug development.
Provide epidemiological data for the target condition, current treatment landscape, existing challenges, how this product addresses these issues, its key features, and the significance of this proposal.
(III) Rationale
1. Prescription Source
Provide a detailed account of the prescription's origin, application, screening or evolution process, and selection criteria. For prescriptions derived from ancient formulas, specify their exact source, evolutionary history, current understanding, and supporting evidence. If there is existing clinical experience, provide data on efficacy and safety based on actual use. Depending on the application category and product type, support this information with relevant literature or pre-clinical trial data from animal and/or human studies on pharmacodynamics, toxicology, and clinical outcomes conducted during formal new drug development.
2. Discussion on the etiology, pathogenesis, therapeutic principles, and prescriptions for the chief disease and symptoms
Traditional Chinese Medicine (TCM) preparations analyze the etiology, pathogenesis, and therapeutic principles of the target conditions using TCM theory. They also examine the fundamental compounding principles of the prescription—such as the roles of sovereign, minister, assistant, and guide herbs—as well as the constituent ingredients, to demonstrate the rationality of the formulation.
Natural medicine formulations should provide a rationale for the proposed indication based on existing research data. The drug's mechanism of action must align with the disease stage, subtype, and clinical presentation of the target indication to justify its use. Additionally, the submission should outline the planned next steps for clinical development.
3. Literature Review
The literature review should focus on the research objectives of the dosage form, covering historical and contemporary sources related to its therapeutic indications and prescription composition. This will further substantiate the scientific rationale for the project. Ensure that cited references are authentic, relevant, properly sourced, credible, and reliable.
Note: For applications involving Chinese herbal medicines, new medicinal parts, substitutes for Chinese herbs, or natural drugs, the rationale should primarily include a comprehensive review of historical and contemporary literature.
(4) Analysis of Innovation and Feasibility of the Declared Product
1. Analysis of the current status of research, production, and use of relevant varieties domestically and internationally
Provide analysis of domestic and international research, production, and usage status for products with indications similar to this product's approved therapeutic indications, as well as for drugs with formulas similar to this product's composition, to demonstrate its innovativeness.
Comparison with similar varieties covered by existing national standards for 2.
Provide comparative data with existing national standards for similar varieties to demonstrate their characteristics and development significance.
3. Feasibility Analysis
Discuss the scientific basis of this study, the rationality of the prescription composition, the feasibility of future research, and market prospects.
IV. References
1. ICH Regulatory Technical Documentation Compilation
2. "Drug Registration Management Measures" (2002)
3. Good Clinical Practice (1999)
4. Ideas for selecting topics in new Chinese medicine drug research. Zhang Tiejun. Chinese Herbal Medicines 1998 Year; 29 (12); 846.
5. Approval Process and Documentation Preparation for New Traditional Chinese Medicine Drugs. Wang Yuxi, Hu Jiahong, Zhuang Wei. Journal of Pharmaceutical Practice 1996; 14(3): 190.
6. Discussion on Prescription Rationale and Review of New Traditional Chinese Medicine Drugs. Zhang Zhen, Lu Zhizheng, Ji Liangchen, et al. New Traditional Chinese Medicine Drugs and Clinical Pharmacology 1995; 6 (2) 1.
7. Preclinical Research on New Chinese Medicines - Yin Zhi, Gao Hongli, Zhang Huai Journal of Hubei Minzu University (Medical Edition) 2001, 3; 18(1)
8. Basic Requirements of Traditional Chinese Medicine Theory and Prescription Design for New TCM Drug Research Zhou Zhongying New TCM Drugs and Clinical Pharmacology 1996; 7 (4); 1
V. Drafting Rationale
1. Core principles of this drafting guideline
This set of writing guidelines outlines the fundamental requirements and principles for preparing clinical study data when registering traditional Chinese medicine (TCM) and natural medicines for clinical trials. In accordance with the "Drug Registration Management Measures" implemented starting from 2002 year, 12 month—which specifies the registration categories and submission document requirements for TCMs and natural medicines—this section primarily pertains to Part 3: "Rationale and Basis."
2. Necessity of Drafting This Principle
The development of new traditional Chinese medicines (TCM) and natural drugs differs significantly from that of new chemical entities. The primary distinction lies in the fact that, prior to initiating formal pharmaceutical, pharmacological, and clinical studies for most TCM and natural drug candidates, substantial pre-existing research on safety and efficacy—encompassing clinical use, pharmacodynamic effects, and toxicology—is often already available. These foundational data points are critical determinants of a drug's development potential, risk profile, and technical requirements, and they constitute a key focus area for regulatory review, particularly for traditional compound formulations with extensive human use history and modern compound preparations. Consequently, thoroughly reviewing, summarizing, and analyzing existing research foundations before commencing formal studies is an essential component of TCM and natural drug development. It serves as a critical basis for regulators to determine whether registration dossiers support the transition to clinical trials or require additional technical studies; this step is indispensable, not optional. In registration submissions for TCM and natural drugs, this foundation is documented through relevant medical theories and literature within the clinical section. Therefore, it is necessary to establish clear guidelines for drafting these medical theories and literature sections. This ensures that registration dossiers adequately reflect the drug's research foundation, the developer's rationale and methodology, objectives, and justification. Such documentation enables regulators to assess the strength of evidence regarding safety and efficacy, evaluate the extent to which existing data supports entry into clinical trials, and define corresponding technical requirements. To meet these standards, developers must adhere to the unique principles of TCM and natural drug development, prioritize project initiation and selection to proactively mitigate risks, and focus their efforts on writing medical theory and literature that robustly substantiate the drug's safety and efficacy.
3. Purpose of Drafting Principles
3．1 establishes a platform for the drug review agency and the research institution to communicate on relevant issues.
The review of research and technology for new Chinese medicines is an exploratory and forward-looking endeavor. Due to its complexity and diversity, it cannot be confined by a rigid framework. However, the technical development of new drugs follows inherent objective laws and general principles. Whether in drug development or regulatory evaluation, these fundamental principles must be followed, including clinical submission data as required by the new "Drug Registration Management Measures." Submission documents should clarify the rationale and execution of the sponsor's clinical research program. The guidelines for "Medical Theory and Literature Compilation for Clinical Trial Applications of Traditional Chinese Medicines and Natural Drugs" establish the essential requirements and common standards for this aspect of new drug development. These requirements define both the obligations of sponsors and the key focus areas for technical reviewers. Ultimately, these principles serve to create a platform for dialogue between evaluators and developers, laying the foundation for substantive discussions on specific products.
3. 2 Guide pharmaceutical R&D units to follow the principles of traditional Chinese medicine development and prioritize topic selection and project initiation before clinical studies.
The clinical section of preclinical submission materials should document the rationale and strategic approach for selecting and initiating drug development projects. It must outline the intended objectives, clarify the therapeutic indications under consideration, and describe the expected mechanism of action and distinguishing characteristics of the drug. Essentially, this section serves as a comprehensive explanation of the development process and foundational strategy by the sponsor.
Inadequate preclinical research or premature development without thorough investigation often results in insufficient justification, thereby increasing development risks. Conversely, prioritizing project initiation work, rigorously assessing potential risks, and proactively addressing challenges identified in pharmacodynamics, toxicology, and other relevant studies will strengthen support measures and mitigate development risks.
This principle is particularly critical for drug development, especially for traditional Chinese medicine (TCM). Adhering to these fundamental principles ensures that sponsors prioritize project selection and initiation before advancing drug development, enabling them to proactively reduce associated risks.
3. 3 Highlight the basic principles of clinical drug evaluation
The core philosophy of this drafting principle is to reflect the fundamental principles and requirements for evaluating new Chinese medicines in preclinical and clinical contexts. By reviewing preclinical submission materials, it emphasizes evaluation of the drug development process and the extent to which study results support the efficacy and safety of the intended indications. It also highlights assessment of the rationality of the formulation, appropriateness of indication selection, and clarity of research objectives, laying the foundation for subsequent comprehensive drug evaluation. For instance, a traditional Chinese medicine (TCM) compound formula derived from clinical experience with a solid research background will provide significantly stronger evidence for the safety and efficacy of its indicated uses compared to a single active component with no clinical history. Therefore, their pharmacological and toxicological studies should differ accordingly.
4. Key characteristics of this writing guideline
The drafting principles outlined here serve as guidelines. Due to the unique nature of research on traditional Chinese medicines and natural drugs—and given the limited experience currently available in their development and regulatory review—these principles require further refinement based on accumulated experience.
The drafting principles for this initiative aim to prevent the overly strict and formalistic requirements of the past, while ensuring the standardization of drug submission documents. They also guide development teams to prioritize clinical activities prior to new drug development—such as topic selection, formulation screening, and indication determination—to address previous gaps in medical research during preclinical stages. This ensures robust support for the safety, efficacy, and clinical feasibility of the intended indications, thereby facilitating the transition to formal clinical trials.
6. Explanation of First Draft Revisions and Finalization
This second revision was finalized following expert discussions at the Guangzhou meeting from 11 to 30, 29, building on the first draft developed in month 10 of year 2003. While the core content remains unchanged, the structure and formatting of the writing principles have been revised, and the wording has been refined for clarity.
However, there is some disagreement regarding the name of these drafting guidelines. For now, we are using the title "Drafting Guidelines for Medical Rationale and Literature Materials in Applications for Clinical Studies of Traditional Chinese Medicines and Natural Drugs." This will be further refined in future discussions.
VI. Author
Research Group on Principles for Writing Medical Rationale and Literature Data for Applications of Chinese Medicines and Natural Drugs to Conduct Clinical Studies