Guidance for the clinical evaluation of traditional Chinese medicine-induced liver injuryIssued by China Food and Drug Administration

Abstract

Drug-induced liver injury (DILI), defined as liver injury caused by a drug and/or its metabolites, is a common clinical adverse drug reaction1, 2, 3, 4. This type of injury can cause acute liver failure and even death in severe cases5. DILI accounts for many drug warnings and is an important cause of failure in the clinical development of new drugs and new forms of traditional Chinese medicine (TCM). Thus, liver injury from drugs has attracted close attention from medical professionals, the pharmaceutical industry, and the general public6, 7, 8. For thousands of years, TCM has contributed to the prevention and treatment of disease, to the development of the Chinese nation, and to the quality of life of Chinese people. For many individuals, TCM remains an essential component of modern life. However, continuous improvements in monitoring adverse drug reactions/events (ADRs/ADEs), along with increased TCM use worldwide has frequently identified TCM-associated safety issues such as DILI9, 10. This situation imposes serious obstacles to the research and development of new, safe TCM drugs and the viability of TCM industries. Due to the lack of specific diagnostic indicators, an exclusion diagnosis of DILI has been commonly adopted, but this approach has shown a high rate of misdiagnosis. TCM DILI is often overlooked because of the pharmaceutical complexity of TCM, the limited basic information on the quantities of TCM components, as well as the increasingly common use of drug combinations. The causal relationship between liver injury and TCM is also difficult to clarify. In addition, potential TCM toxicity is often overlooked by the public since TCM preparations are commonly regarded as “natural, without toxic and side effects”. For these reasons and because developers and enterprises have paid insufficient attention to ADRs, the prevention and control of TCM safety risks is extremely difficult11. Therefore, the establishment of an objective and scientific technical system for assessing and identifying TCM DILI is needed. To this end, with strengthening the risk management of the entire drug life cycle as the main goal, the China Food and Drug Administration (CFDA)of China organized experts in related fields to develop the Guidance for Clinical Evaluation of Traditional Chinese Medicine-Induced Liver Injury. This task was accomplished by integrating the consensus of Chinese and international experts with research progress in the fields of medicine and pharmacy as well as in clinical and scientific research. This document aims to provide advice and assistance to relevant institutions and personnel in identifying the risk signals of TCM DILI; scientifically assess the causal relationship between patients׳ liver injury and TCM; effectively reduce misdiagnosis; fully evaluate the safety, risks and benefits of relevant TCM; and purposefully develop prevention and control measures for TCM DILI. These activities are needed to reduce the failure rate of new TCM drug research and development (R&D) and the risk of clinical use as well as to promote a viable TCM industry in China. This guide is designed for the evaluation of DILI and for risk control throughout the entire life cycle of TCM products, including the research and development stages of new drugs and post-marketing stage. It should also be used for TCM R&D, as well as by medical and regulatory agencies. Each drug marketing authority must carry the main responsibility for the product and not only strengthen the management of the entire lifecycle of the product but also take realistic and effective risk control measures to ensure the safety of public drug use. The TCMs (including ethnomedicines) in this guide consist of the TCM preparations that are being studied and those already on the market. This guide can be used as a reference for clinically used TCM decoctions and tablets, formulated TCM granules, TCM extract, homemade herbal medicines, TCM-containing health products and TCM health foods as well as relevant excipients. Many problems that urgently require in-depth study and solutions still exist in the field of TCM DILI. This guidance will be continuously revised and improved in accordance with research progress on TCM DILI and regulatory requirements.