Letter to the editor: Comment on the Regulatios of the Simplified Registration and Approval Management for Compound Recipe of Classical Prescription of Traditional Chinese Medicine

To the Editor:

On Oct 9, 2017, China Food and Drug Administration announced¹ the Regulations of the Simplified Registration and Approval Management for Compound Recipe of Classical Prescription of Traditional Chinese Medicine (Exposure Draft) which has been stirring up intense debate in the West. The article China to Roll Back Regulations for Traditional Medicine Despite Safety Concerns lately published on Nature² has raised worldwide attention by stressing its worries over the safety issue of traditional Chinese herbal medicines. However, we noticed that classic Chinese herbal formulations with long-term traditional use are not yet well known to the Western world. Hereby we intend to elaborate on a clearer picture of classic Chinese herbal formulations and to offer a better understanding to the western researchers.

In our study, the classic Chinese herbal formulations only refer to those quoted from the ancient Chinese medical classics prior to 1911 which have conformed with the same stringent examination, regulation model, and approval standards as other medications in China since the implementation of “Provisions for Drug Registration” in 1985. In 2016, the China Food and Drug Administration (CFDA) approved only two types of new classic Chinese formulations, yet hundreds of chemical and biological drugs. Effects of classic Chinese herbal formulations, though being proved by hundreds of years' clinical application, have to over and over again go through time-consuming and costly lab tests. It is the indiscriminate regulation that slows down the development of classic Chinese herbal formulations. In fact, the traditional herbal medicines and modern biochemical drugs differ both in pharmacology and in applications history. Therefore we suggest that the current regulation policy for chemical drugs should not be applied to Chinese herbal medicines without any adjustment. Based on this characteristic, CFDA plans to adopt a simplified registration and approval management. This is beneficial to speed up the launch of new drugs of Chinese herbal medicines, reduce the research and development cost, ease the burden of medical care, achieve WHO's accessibility and affordability on traditional drugs and promote the goal for TCM to serve human health³.

1. Minimizing clinical trials is an internationally customary regulation for traditional herbal medicines

The registration and regulation of traditional herbal medicines are different from chemical drugs in many countries. The efficacy of traditional herbal medicines is mainly proved by long-standing clinical use in mass population and thus a simplified registration procedure for herbal medicines is internationally accepted.

The European Union Herbal Medicines Directive⁴ notes that with long-term traditional application, it is necessary to provide a specially simplified registration procedure for herbal medical products. The Action Plant for Herbal Medicines (2010–2011) published by European Medical Agency (EMA) on June 11, 2010⁵ presented that recommendations on extending the scope of simplified registration procedures have been made to European Parliament. If this proposal is adopted, the simplified registration procedure will be extended to other traditional products, including those drugs of animal origins. The Ministry of Health and Welfare, Japan6, 7 approved 210 classical prescriptions of Kampo medicines without clinical trials produced by Japanese enterprises. The Ministry of Health, Korea stipulated that pharmaceutical factories could produce 11 recipes from its medical classics without clinical trials. In the U.S.A., herbal medicinal products⁸ have been classified as dietary supplements and are widely sold in market with no need for clinical trials (See Table 1 for details). With an application history of hundreds and even thousands of years, herbal medicine efficacy and safety have been supported by long-term clinical practice. Considering above situation and experiences, China plans to adopt a simplified registration approach to classic Chinese herbal formulations, which is in conformity with international acknowledgment.

Table 1.

Examination and approval requirements for herbal products in different countries and regions.

Item	Japanese Kampo	Herbal medicine in European Union	The USA		Chinese classic formulations
			Dietary supplement	OTC drugs
Relevant laws and regulations	Acknowledged Benchmark for GeneralKampo Preparation, 1974; Treatment on Medical Kampo Preparation,1980	DIRECTIVE 2001/83/EC, Directive2004/24/EC	Dietary SupplementHealth and Education Act of 1994	Botanical DrugDevelopment, Guidance for Industry，2016	Registration and management of TCM,2007; Supplementary Regulations on the Registration and management of TCM, 2008
Source of products	Classical herbal formulations included in1974 quoted from ancient medical classics such as “Treatise on Cold Pathogenic and Miscellaneous Diseases”, etc.	Tradition herbal medicine	Herbal medicine ordietary supplement	The drugs listed in OTCMonographs	The classic Chinese formulations are quoted from the ancient Chinese medical classics prior to 1911
Product requirements	In principle, the product shall not containtoxic or rank toxic drugs.	Those with a traditional usage for over30 years and literature proof or expert evidence, including those with a traditional usage for over 15 years in European Union countries.	Do not claim to beable to diagnose, treat, or prevent disease	The drugs conform toOTC monograph	The product shall not contain toxicmateria medica or ingredients, and the scope of application does not include emergencies, infectious diseases, pregnant women or infants.
Pharmaceutical research	Data of standard decoction, preparation,quality, etc.	Physical, biological, and microbiologicaltests are required, the quality conforms to the standards of the European pharmacopoeia	Not required	The drugs conform toOTC monograph	Data of standard decoction, preparationresearch, and quality studies, etc.
Toxicological research	Not required	Generally not required	Not required	Not required	Non-clinical safety evaluations arerequired
Clinical research	Not required	Not required	Not required	Not required	Not required
Approval	Registration	Registration	No need forexamination and approval	No need forexamination approval	Registration

2. Non-clinical safety and quality control studies are still required

The research and development process for new classic Chinese herbal formulations differs from that of chemical drugs and biological drugs. No chemical or biological drug is supposed to be applied to clinical use before it is approved by tests in lab, concerning the efficacy and safety issues. Yet the Chinese herbal medicines, especially the classic Chinese herbal formulations with its longstanding popular use, have already established a solid foundation for their reputations.

However, stringent stipulations are still applied to the registration scope of classical prescription of Chinese herbs. It specifies that only those recipes for traditional Chinese herbal medicines listed in the “Ancient Classical Prescription List” can be adopted to prescription. After thorough consideration only one hundred classical herbal formulations are to be included initially, all these were screened with rigorous criteria. The purpose is to make sure that those selected classic Chinese herbal formulations do not contain any known toxic materia medica or ingredients.

In addition, there is a strict requirement for the safety of classic Chinese herbal formulations. Despite its long-standing massive use, systematical and profound non-clinical safety studies are expected for every classical formulation. Currently, the safety protocol for newly developed classic Chinese formulations conforms to the GLP standard. The conventional contents and technical requirements for the safety evaluation are the same as those for chemical drugs.

3. Chinese herbal medicines with a longstanding traditional use act relatively safer in the clinic

Chinese herbal medical products are widely used in the clinic. The reported adverse reaction of traditional Chinese herbal medicines accounts for only 17.3% of the total adverse drug reaction, whereas that of chemical drugs accounts for more than 81%⁹. Generally, Chinese herbal medicine presents to be safer than chemical drugs. The adverse effect of aristolochic acids has drawn attention to the entire TCM field. The toxicological tests of Chinese herbal medicine are strongly encouraged by Chinese government and many of them are already being undertaken. In the past decades, Chinese government has been supporting the researches on the toxicology of both single Chinese herbs and TCM patent prescriptions. The mechanism of how Chinese herbs function in human body was unveiled and a systematic structure of the toxicology and pharmacology attributes of both individual Chinese herbs and herbal prescription compounds have already been built up.

Chinese herbal pharmacology is a fundamental carrier of Chinese culture and civilization. The economic entity of health industry, which took TCM as its core, has achieved a market share of nearly USD 3000 billion annually. TCM is an inseparable chain in Chinese medical security scheme and the world medical reform calls for "China Program". Marveled at the discovery of artemisinin, the world has been expecting more from TCM.