Pains of TCM Injections, and Imminent Reevaluation of TCM Injections

Author: zhulikou431

The State Drug Administration of China (SDA) announced in the evening of May 29, 2018 the decision to revise the package insert of Bupleurum injection (as shown in the following figure). Besides adding warning and revision of adverse reaction, contraindication, and notice, what draws the greatest public attention is the "contraindicated for children" in the contraindication, for which the main reason is the multiple adverse reactions of the Bupleurum injection (see the following figure).

There are mainly three categories of TCM injection: one is the heat clearing and detoxifying category, mainly used to treat respiratory system diseases; two is the blood circulation promoting and stasis removing category, mainly used to treat cardiovascular and cerebrovascular diseases; three is the tonifying and qi-correcting category, mainly used to treat tumors. According to the data in 2017 Annual Report for National Adverse Drug Reaction Monitoring, among the suspected pharmaceutical products involved in the adverse drug reaction/event reports in 2017, the top 10 categories by TCM cases were separately: blood circulation promoting and stasis removing drugs in the blood-regulating formulae (31.1%), heat clearing and detoxifying drugs in the heat-clearing formulae (9.5%), qi and yin tonifying drugs in the tonic formulae (8.7%), cold drugs in the resuscitation formulae (8.2%), cold-pungent and diaphoretic drugs in the exterior releasing formulae (5.6%), heat clearing and dampness removing drugs in the dampness eliminating formulae (4.9%), wind dispelling and dampness eliminating drugs in the dampness eliminating formulae (3.0%), heat clearing and phlegm eliminating drugs in the phlegm-expelling formulae (2.3%), qi-tonifying drugs in the tonic formulae (1.7%), and qi-supplementing and blood-activating drugs in the blood-regulating formulae (1.5%); furthermore, TCM injections and TCM oral preparations separately accounted for 54.6% and 37.6%.

The safety problems of TCM injections are mostly caused due to adverse reactions thereof, including from the adverse reaction events of the Houttuynia cordata injection and Acanthopanax senticosus injection in the early days, to death event caused by Shuanghuanglian injection in 2009, to the emergency recall of Safflower injections and Xiyanping injections by the former CFDA due to serious adverse events that happened in many places of China in September 2017. The former CFDA announced on September 23 thereafter to halt use of Xiyanping injection.

There are the following root causes for the adverse reactions of TCM injections:

★Blind spot in prescription drug selection during TCM injection R&D: TCM injections are mostly compound products that use a large number of non-statutory varieties not from the pharmacopeia as the raw materials, of which the quality standard, chemical ingredient, and toxicity, etc. lack reference data and standards, directly threatening the quality stability and safety of TCM injections and increasing the risks of adverse reaction occurrence.

★Limitations of clinical trials before the marketing of TCM injections: the limitations mainly show as small number of clinical trial cases and short trial process, etc.

★Low quality standards for TCM injections: the quality standards fail to control the multiple ingredients of the injections.

★Backward production processes of TCM injections: modernization of TCM production is now advocated and some manufacturers have introduced advanced production equipment and improved production processes, however, there are still many old production processes of which the most serious impact is the impurity residual in TCM injections, eventually affecting the quality stability and use safety.

★Clinical use of TCM injections lacking standardization: this is also a common problem. The amount of clinical use of TCM injections has been greatly reduced in recent years as the TCM injection varieties are restricted, however, there are still non-standard clinical use phenomena such as irrational combination of Chinese and Western medicines, overdosing, and improper infusion method, dosing method, and infusion speed during the clinical use, which may also cause the adverse reactions.

★Insufficient safety reevaluation after the marketing of TCM injections, which we will focus on today.

As the safety of the TCM injections is questioned, the reevaluation of TCM injections becomes an urgent agenda. Next, let’s review the course associated with the TCM injection reevaluation by taking the opportunity of this revision of package insert of Bupleurum injection.

The following is a figure that summarizes policies of the TCM injection industry in China:

The safety reevaluation of TCM injections basically started in 2009. The former CFDA issued the Notice on Conducting the Safety Reevaluation of Traditional Chinese Medicine Injections (SYJB [2009] No. 359) in 2009, proposing to conduct risk and benefit evaluation of key varieties of TCM injections by stages and in batches, with the first batch to be Shuanghuanglian injection and Shenmai injection, and requiring comprehensive conduct of risk inspections of production and quality control links, effective control over potential safety hazards of TCM injections, organization of comprehensive evaluations to guarantee safety, effectiveness, and quality controllability of TCM injections, and acceleration of TCM injection standard improvement to guarantee product quality. Thereafter, the second batch of varieties for reevaluation published in the Notice on Conducting the Safety Reevaluation of Traditional Chinese Medicine Injections in 2010 included Houttuynia cordata injection and Yujin Injection.

Former CFDA issued the "7 Technical Guidelines for the Safety Reevaluation of the Traditional Chinese Medicine Injections" in 2010, expressly proposing to conduct safety revaluation of TCM injections, which include: the technical guideline for production process evaluation, technical guideline for quality control evaluation, technical guideline for non-clinical study evaluation, technical guideline for clinical study evaluation, technical guideline for risk control ability, technical guideline for risk and benefit evaluation, and technical guideline for risk management plan, however, the relevant department of China has yet started the official review and evaluation of the part of work conducted by enterprises.

The TCM injection reevaluation was officially on the agenda in October 2017. The Opinions on Deepening the Reform of the Review and Approval System and Inspiring Innovation of Drugs and Medical Devices issued by the General Office of the Communist Party of China Central Committee and General Office of the State Council of China on October 8, 2017 proposes that the review and approval of the pharmaceutical product injections will be strict in the future, and the marketed pharmaceutical product injections will be reevaluated, which is expected to be basically completed in 5-10 years.

What is difficult about the TCM injection reevaluation is that the ingredients in such pharmaceutical products are complex and not as clear as those in chemical drugs, and currently there are not many criteria as to the influences of processes on active ingredients during the preparation. Moreover, the clinical data on which the marketing of most TCM injections is based are not quite sufficient.

Based on the above characteristics, the effectiveness, safety, and quality controllability of TCM injections have been of great concern to the pharmaceutical industry. As SDA (former CFDA) restarts the TCM injection reevaluation, the industry and the public are looking forward to that this reevaluation could be gradually conducted on the basis of scientific directions, solid and rich data, and objective and impartial work.

References:

1. Causes for Adverse Reactions of Traditional Chinese Medicine Injections: A Case Study of the "Houttuynia Cordata Injection Event"

2. Annual Report for National Adverse Drug Reaction Monitoring (2017)

3. Relevant guidelines for reevaluation of TCM injections in 2009