Pharmacovigilance in China - Traditional Chinese Medicine

Traditional Chinese Medicine Drug Safety

Monitoring in ChinaAAPS College (Toronto, Canada)

Global Clinical Studies & PharmacovigilancePresented by: Carolina Hung Ho

Professor: Dr. Peivand PirouziPeer-reviewed by: TBD

March 20, 2016

OVERVIEW

Part I: General Pharmacovigilance in China1. Timeline2. Development of Drug Safety Monitoring System in China3. Organizational Structure

Part II: TCM Pharmacovigilance in China1. Overview of TCM 2. Characteristics and Risk Factors 3. TCM Drug Safety Monitoring4. TMCI - Traditional Chinese Medicine Injections 5. Global Impact of TCM

OVERVIEW

Part I: General Pharmacovigilance in China

1. Timeline2. Development of Drug Safety Monitoring

System in China3. Organizational Structure

1. Timeline: Pharmacovigilance in China

Prior to 1989 -Literature reviews and case reports from hospitals and patients

1989 Establishment of SFDA, ADR Monitoring System, & ADR Monitoring Center

1998 WHO affiliation

2011“ADR Reporting & Monitoring Provision” Revised(~400 local centers)

2001 Nationwide ADR Monitoring Center (~32 provincial centers)

Indicates major advances in the Chinese pharmacovigilance system

2. Development of Drug Safety Monitoring in China

In the early 1980’s, Chinese Ministry of Health started to carry out pilot projects to monitor ADR. 10 monitoring units; mainly to collect case reports from physicians and hospitals.

In 1989, the Chinese State Food & Drugs Administration (SFDA) was established (=FDA, HC)

The Adverse Drug Reaction Monitoring System (= FAERS, Canada Vigilance System) Founded the National ADR Monitoring Center A voluntary reporting system Collects adverse drug reactions for Western and TCM drugs

In 1998, it formally joined the WHO International Drug Monitoring Program

Facts: China submits cases of ADRs, known as ICSRs, to WHO global database VigiBaseTM, along with 122 members.

2.Development of Drug Safety Monitoring in China

ADR monitoring was strengthened in terms of: Legal framework Monitoring systems IT applications Administrative control Capital investment Other aspects

Figure 1: Creating a nationwide safety monitoring system with an unified network for reporting adverse drug reactions in China


Gradual improvement in laws and regulations Drug Administration Law of the

People’s Republic of China (2001) “The Law” contains the mandate

for drug safety surveillance Regulation for Administration of

ADR Reporting & Monitoring (2004) Describe responsibilities of

regulatory authorities, drug manufacturers, distributors, and medical institutions.

Describe standardized procedures for reporting, evaluating, and managing ADRs.


Expanding their monitoring network By the end of 2002, provincial

ADR Monitoring Centres had been set up in 32 provincial level.

By the end of 2010, China had set up 400 centres in total.

Figure 2: China has 34 provincial-level administrative divisions.


Online reporting network becoming available The quality of ADR reports

has gradually becoming more standardized

Faster receipt of these reports, allowing prompt actions to be taken with emerging safety issues

Thereby, establishing a nationwide surveillance system.


Since 1998, the number of ADR reports has increased dramatically.

Figure 4: Incidence of ADR reports collected by the National ADR Monitoring Center in China (Yan-Min, SFDA).


In 2015, SFDA released 2014 Annual Report for National Adverse Drug Reaction Monitoring:

“In 2014, the national ADR monitoring network received 1.328 million ADR/ADE case reports, including 341,000 new and serious ADR/ADE cases (25.7% of the total)…The Annual Report indicates that China’s ADR reporting coverage was increased, the ability to discover and collect ADR information was enhanced, and the public’s drug safety awareness was further improved.”

(SFDA, 2015)


The ADR Information Bulletin (ADRIB) Issued by SFDA since 2001 By 2014, public has been made aware of nearly 109

drugs with serious problems Prompt measures taken to ensure patient safety

Modification of the package inserts (= Product Reference)

Conversion of OTC drugs prescription drugs Withdrawal from the market


Chinese Journal of Pharmacovigilance Academic journal covering a wide range of safety

issues: Official regulations about drug safety Vaccine safety Medical device safety New developments in drug safety research Issues in international pharmacovigilance Post-marketing surveillance

3.Organizational Structure of ADRMonitoring System in China

Figure 3: Structures and procedures for the ADR monitoring and reporting network in China (Du et al., 2008)

BUT…

What About Traditional Chinese

Medicine?

OVERVIEW

Part II: TCM Pharmacovigilance in China1. TCM – An Overview2. Characteristics and Safety Risk Factors3. TCM Drug Safety Monitoring

4. TMCIs - Traditional Chinese Medicine Injections Article: Adverse Events to Houttuynia Injection (Wang et al.,

2010)

5. Global Impact of TCM and TCMIs

1. Traditional Chinese Medicine: An Overview

TCM relies on a combination of herbs for:1. Health optimization2. Disease prevention3. Disease treatment

About 5800 substances currently in use; deriving from plant, animal, and mineral origin.

Each herbal practitioner develops a formula that is very unique and highly personalized.

TMC have been traditionally prepared in many ways: soup, pellet, cream, powders, syrups, etc.

1. Traditional Chinese Medicine: An Overview

Over the recent years, advances in pharmaceutical technology has led to modernization/rediscovery of TCM:

Patent formulas - are pre-made herbal formulations in pill or tablet form (the most widely used form of TCM outside of China).

Injections – although they can be traced back to 1940’s, recent developments allow for: Use as an add-on treatment to many standard therapeutic

treatments (e.g. infections, late stages of cancer, chronic heart failure)

Rapid effects due to IM, IV route of administration. “Fewer side effects” while retaining characteristics from the herbs.

2. Characteristics of TCM & Risk Factors

The quality of the drug is one of the most important factors affecting TCM drug safety

Factors related to drug quality include: Raw herbals – improper naming Processing Storage Inactive ingredients Manufacturing Improper labeling/packaging Limitations of pre-marketing safety studies Adulterated and counterfeited drugs

2. Characteristics of TCM & Risk Factors

Safety Factors Related to Clinical Use:

Lack of TCM-theoretical guidance Failure to adhere to the prescribing indications Inappropriate combination with Western medicine Inappropriate route, dosing, and timing Incorrect preparation Individual factors (i.e. irrational use, improper use)

3. Pharmacovigilance for TCM in China

There is NOT a separate PV system for TCM drugs

ADR/ADE reports are handled by the ADR Monitoring System

10% - 15% of total ADR reports are TCM-related. 10% - 15% of these are unexpected, serious case

reports 99.7% are mainly re-formulated products

4. TCM Injection

Following the establishment ADR Monitoring Center by SFDA in 2001, ADR cases from TCM injections have been steadily increasing in recent years.

In 2005, TCM injection accounted for 83.7% in TCM-related ADR reports.

In 2011, SFDA received a total of 852,799 reports of ADRs/ADEs, including 65,572 cases of TCM injections reports, a 35% increase over 2010.

(Yongyang et al., 2014)

4. TCM Injection: Translating Evidence in Safer Healthcare

Introduction: Study Details (1)Wang et al. (2010). Adverse events to Houttuynia injection: A systematic review. Journal of Evidence-Based Medicine. 3: 168-176. doi: 10.1111/j.1756-5391.2010.01091.x

Link: http://www.sciencedirect.com/science/article/pii/S0254627215300704


Introduction: Background (2) Houttuynia injection is a TCM used widely in China for treating

infections. Cheap and rapid anti-inflammatory effects In 1978, its intramuscular injection was approved In 1994, its intravenous formulation was approved

Plant: Houttuynia cordata (Pin Yin: Yu Xing Cao)

Houttuynia injection (TMC)


Methods: Study Design and Objective

Design: Literature Screening Objective: 1. To systematically investigate the safety of

Houttuynia injections-associated ADRs2. To contribute to the post-marketing re-evaluation

and clinical practices of this injection


Methods: Study Setting Multiple electronic databases:

PubMed (1978 – June 2010)

EMBASE (1978 – June 2010)

Chinese National Knowledge Infrastructure (CNKI) (1989 – June 2010)

Chinese Science and Technology Journal (1989 – June 2010)

Chinese Biomedical Disc (CBMdisc) (1978 – 2010)

Search criteria: “Houttuynia cordata”, “Houttuynia injection”,

“response”, “role”, “adverse reaction”, “adverse event”, “allergy”, “side effects”.


Methods: Data Collection (1) Selection Criteria:

Randomized controlled trials (RCTs) Non-randomized controlled trials (non-RCTs) Case-control studies Cross-sectional studies

Two (2) researchers independently screened the studies for eligibility

Any discrepancies was resolved by third party Endnote X2 was used to manage included literature

4. TCM Injection:

Figure 5: Flow Diagram of Study Screening (Wang et al., 2010)


Methods: Data Collection (2) Collect data based on:

1. Patient information of ADR/AE cases (e.g. age, gender, primary diseases, allergic history)

2. The dosage, duration, route of administration of injection

3. Concomitant intervention4. ADR/AE information and its severity (using WHO

coding standards)


Methods: Data Analysis Descriptive analysis for the ADRs/AEs, including

allergic history, primary diseases, administration of injection, concomitant medications, the involved organ systems, and severity of ADR/AE

Chi-square analysis for ADRs/AEs associated with different routes of injections

Relative Rations (RR) with 95% CI using statistics software Stata 9.1


Results: Key Findings (1) A total of 645 articles included, with a total of 1232

ADR cases reported. Respiratory diseases accounted for 52% of ADR cases Multiple organs affected: respiratory (37%), skin

(35%), digestive (25%), circulatory (25%), nervous (24%)


Results: Key Findings (2) Serious ADRs accounted for 23% of total ADR cases. Anaphylactic shock accounted for 59% of the serious ADR cases (Grade I). All

cases of death were caused by allergic shock except for one (10/11 cases). Fastest onset of ADR = 1 minute after injection Of all ADR cases, 20% reported previous allergies Among ADR cases, H. injection was commonly used together with cephalosporin,

penicillin, and macrolides. Higher ADR risk when taken with macrolides (RR=8.80, 95% CI 6.12 to 12,65, P

< 0.0001) Higher ADR risk when administered intravenously than intramuscularly (OR =

6.86, 95% CI 1.88 to 56.95, P= <0.00016)


Conclusions: Main Points Respiratory system was the most common system

treated in H. injection ADR cases It was also the most common site of ADR symptoms Cases of ADRs from H. injection is rare, but serious Intravenous injection, and combination with antibacterial

agents increases the ADR risk of H. injection. Precautions should be taken to prevent anaphylactic

shock


Measuring harm: Cases of ADR reports from 1978 till 2010 from research databases.

Understanding the causes: Unknown mechanism; Houttuynia may contain allergens.

Identifying solutions: In September 2003, warning was issued for H. injection In June 2006, suspension and withdrawal of all H. injections from the market

Evaluating impact: Since banning H. injection, cases of ADRs have dropped significantly.

Translating Evidence into Safer Care Since 2006, IM injection has been allowed back as a prescribed medication Changes to product reference information

“Warning: This product may cause some serious allergic reactions” Strict quality control and processing (GAP, GMP practices) Enforce ADR monitoring Raise awareness about the irrational, improper use and concomitant medications

4. TCM Injection: Translating Evidence in Safer Healthcare ADR reports for Houttuynia injection has dropped significantly

after SFDA suspended and withdrawn these TCM products from the market in 2006.

Figure 6: Number of adverse drug reaction cases in relation to study distribution by publication year and design type. (Wang et al., 2010)

This event translates to successful

implement risk management strategies by

SFDA

5. What is the impact of TCM on the global market? Worldwide use.

e.g. raw materials from herbs formulated into capsules, supplements, and injectable.

Potential impact on healthcare. e.g. Warfarin and Gingko Biloba (herb-drug interactions)

Opportunity for new drug development e.g. Add-on treatment to standard therapy TCM injections widely researched Houttuynia

injection

Demand for QUALITY and SAFETY of TCM-related products as global market increases.

5. What is the impact of TCM on the global market?

In USA:

“In 2010, it is estimated that approximately 25% of botanical investigational new drug (IND) applications submitted to the FDA were derived from TCM herbs.” (Xu et al., 2013)

In Europe:

“Chinese herbal products are important for Europe because after Asia, Europe is the second largest import/export market of these products.” (Pelkonen et al., 2014)

5. What is the impact of TCM on the global market?

In Canada: 71% of Canadians have

used natural health products (includes TCM)

12% of Canadians who use natural health products report that they have experienced unwanted side effects (ADRs)

Only 41% of Canadians who experienced unwanted side effects (ADRs) to natural health products reported them.

TCM are subject to Natural Health Products Regulations by Health Canada

Table 1: List of TCM medicinal ingredients prohibited in Canada

(Health Canada, 2015)

Particular Issues of Interest Underreporting is a major challenge for ADR reporting in China Cultural, economic, and demographical factors.

On the News:China’s Vaccine Scandal

Link :http://www.bbc.com/news/world-asia-china-35878624

On the News…Chinese Vaccine Scandal

Sections selected from BBC News: Chinese authorities have pledged to crack down on the black market sale of

vaccines after a case was made public involving nearly $90 million worth of illegal vaccines that are suspected of being sold in dozens of provinces around the country.

The case, which involves vaccines against meningitis, rabies and other illnesses, underlines the challenge the world's second-largest drug market faces to regulate its fragmented supply chain, even as Beijing looks to support home-grown firms.

The vaccines, which police said were made by licensed producers, were not kept and transported in the required cold chain conditions, which could mean that patients taking them could suffer severe side effects or even death.

The mother - a former doctor - and daughter were detained last year (April 2015), but the case was not widely publicized until now (March 2016).

On the News: China’s Vaccine Scandal

“The time it took to announce action, sparked anger amongst people in China, who questioned why the authorities had not alerted the public earlier”. (BBC News)

On the News: China’s Vaccine Scandal Li Guoqing, head of China’s SFDA,

bluntly admitted China’s problem: “There are certain loopholes in

our regulatory work…” “There are dead spaces and blind

zones for regulation and inspection.”

“At present our country has 12,000 drug wholesalers, 5,000 production firms and more than 400,000 drug retailers. There aren’t even 500 people with the aptitude to inspect drugs.”

Figure 7: Officials of the State Food and Drug Administration (SFDA) checking the vaccines stored in the local Centre for Disease Control (CDC) in China, on (EPA, 2016)

SUMMARY ADR Monitoring System in China is relatively new Looking up to the more established FDA and EU to

adopt policies However, TCM presents a unique challenge for China Knowledge of TCM safety is experience-based rather

than evidence-based Quality remains as the #1 safety issue TCM injections account for majority of TCM-related

ADR/ADE reports

Improving the Safe and Rational Use of TCM Injections

Enforce the quality of TCM Good Agricultural Practices (GAP) Good Manufacturing Practices (GMP)

Promote quality research of TCM Good Practice in Traditional Chinese Medicine Research in the Post-

Genomic Era consortium, widely known as GP-TCM Funded by EU in 2009 as a 3.5-year project Look into the complex TCM formulations – MOAs and QC

Enforce ADR/ADE reporting Manufacturers, distributors, hospitals, and research institutions

Increase awareness regarding cautious and safe use of TCM Healthcare practitioners, herbal practitioners, and the general public

THANK YOU for your attention!

Thoughts to keep in Mind:

“Traditional use, however, is only an indication but certainly not a proof of safety”

(Xu et al., 2013)

“Traditional use of so-called “natural products” is, for the general public, often erroneously believed to be innocuous because they are “natural”.

(Xu et al., 2013)

ACKNOWLEDGMENTSThis presentation has been peer-reviewed by the following individuals prior to publication:

REFERENCES CFDA releases 2014 Annual Report for National Adverse Drug Reaction Monitoring. (2015). Retrieved March 25, 2016, from http://eng.sfda.gov.cn/WS03/CL0757/124601.html

China Vaccine Scandal: 37 Arrested. (2016). BBC News. Retrieved March 25, 2016, from http://www.bbc.com/news/world-asia-china-35878624

Drug and Health Products:Traditional Chinese Medicine Ingredients (TCMI). (2015). Health Canada. Retrieved March 25, 2016, from http://webprod.hc-sc.gc.ca/nhpid-bdipsn/atReq.do?atid=tcm

Du, W., Guo, J., Jing, Y., Li, X., M. C., Kelton, L. (2008). Drug safety surveillance in China and other countries: a review and comparison. International Society for Pharmacoeconimics and Outcomes Research (ISPOR)

Laws and Regulations. Chinese State Food and Drug Administration. (2016). Retrieved March 25, 2016, from http://eng.sfda.gov.cn/WS03/CL0758/

Natural and Non-prescription Health Products. (2015, May 01). Retrieved March 25, 2016, from http://www.hc-sc.gc.ca/dhp-mps/prodnatur/index-eng.php

Pelkonen, O., Xu, Q., & Fan, T.-P. (2014). Why is Research on Herbal Medicinal Products Important and How Can We Improve Its Quality? Journal of Traditional and Complementary Medicine, 4(1), 1–7. http://doi.org/10.4103/2225-4110.124323

Wang, L., Cui X., Cheng L., Qiang Y., Li T., Li, Y., Deng, S., Shang, H., Bian, Z. (2010). Adverse events to Houttuynia injection: A Systematic Review. Journal of Evidence-Based Medicine. (3). 168-178. doi: 10.1111/j.1756-5391.2010.01091.x

Xu, Q., Bauer, R., Hendry, B., Fan, T., Zhao, Z., Duez, P., Simmonds, M., Witt, C., Lu, A., Robinson, N., Guo, D., Hylands, P. The quest for modernization of traditional Chinese medicine. BMC Complementary and Alternative Medicine. 13(132) 1-11.

Yongyang X, Danhui Y, Mingyan X (2014) Quantitative Pharmacovigilance Modeling for TCM Injections Adverse Event Reporting. J Pharmacovigilance 2:124. doi: 10.4172/2329-6887.1000124

Zhou, Y., Miller, V., Hogan, M., Callahan, L. (2006). An overview of adverse drug reaction monitoring in China. International Journal of Pharmaceutical Medicine. 20(2) 79-85

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Pharmacovigilance in China - Traditional Chinese Medicine