Pharmacovigilance in China - Traditional Chinese Medicine

Traditional Chinese Medicine
Drug Safety Monitoring in China
AAPS College (Toronto, Canada)
Global Clinical Studies & Pharmacovigilance
Presented by: Carolina Hung Ho
Professor: Dr. Peivand Pirouzi
Peer-reviewed by:TBD
March 20, 2016

OVERVIEW
Part I: General Pharmacovigilance in China
1.Timeline
2. Development of Drug Safety Monitoring System in China
3. Organizational Structure
Part II: TCM Pharmacovigilance in China
1. Overview ofTCM
2. Characteristics and Risk Factors
3.TCM Drug Safety Monitoring
4.TMCI -TraditionalChinese Medicine Injections
5. Global Impact ofTCM

OVERVIEW
Part I: General Pharmacovigilance in China
1.Timeline
2. Development of Drug Safety Monitoring System in
China
3. 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 monitorADR.
 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,CanadaVigilance System)
 Founded the NationalADR Monitoring Center
 A voluntary reporting system
 Collects adverse drug reactions forWestern andTCM drugs
 In 1998, it formally joined the WHO International Drug
Monitoring Program
Facts:
China submits cases of ADRs, known as
ICSRs, toWHO global databaseVigiBaseTM,
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

Monitoring 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.

Monitoring in China
 Expanding their monitoring
network
 By the end of 2002, provincialADR
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.

Monitoring in China
 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.

Monitoring in China
 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).

Monitoring in China
 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)

Monitoring in China
 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

Monitoring in China
 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 ADR
Monitoring 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 China
1.TCM – An Overview
2. Characteristics and Safety Risk Factors
3.TCM Drug Safety Monitoring
4.TMCIs -Traditional Chinese Medicine Injections
Article: Adverse Events to Houttuynia Injection (Wang et al., 2010)
5. Global Impact ofTCM andTCMIs

1.Traditional Chinese Medicine:
An Overview
 TCM relies on a combination of herbs for:
1. Health optimization
2. Disease prevention
3. 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 ofTCM:
 Patent formulas - are pre-made herbal formulations in pill or tablet
form (the most widely used form ofTCM 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 ofTCM
& Risk Factors
 The quality of the drug is one of the most
important factors affectingTCM 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 ofTCM
& Risk Factors
 Safety Factors Related to Clinical Use:
 Lack ofTCM-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 forTCM
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 areTCM-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 fromTCM injections have been
steadily increasing in recent years.
 In 2005,TCM injection accounted for 83.7% inTCM-related
ADR reports.
 In 2011, SFDA received a total of 852,799 reports of
ADRs/ADEs, including 65,572 cases ofTCM 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 aTCM 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
(PinYin: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 ADRs
2. 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 andTechnology 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 intervention
4. ADR/AE information and its severity (usingWHO 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% ofADR cases
 Multiple organs affected: respiratory (37%), skin (35%), digestive
(25%), circulatory (25%), nervous (24%)

 Results: Key Findings (2)
 Serious ADRs accounted for 23% of totalADR 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
 AmongADR 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 ofADR 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

 ADR reports for Houttuynia injection has dropped significantly after SFDA
suspended and withdrawn theseTCM 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 ofTCM 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.

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 fromTCM 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)

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 ofTCM medicinal ingredients
prohibited inCanada (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’sVaccine Scandal
Link :http://www.bbc.com/news/world-asia-china-35878624

On the News…
ChineseVaccine 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:
 “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:
 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 theState Food and
Drug Administration (SFDA) checking the
vaccines stored in the local Centre for
DiseaseControl (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 ofTCM safety is experience-based rather than
evidence-based
 Quality remains as the #1 safety issue
 TCM injections account for majority ofTCM-relatedADR/ADE
reports

Improving the Safe and
Rational Use ofTCM Injections
 Enforce the quality ofTCM
 Good Agricultural Practices (GAP)
 Good Manufacturing Practices (GMP)
 Promote quality research ofTCM
 Good Practice inTraditionalChinese 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 complexTCM formulations – MOAs and QC
 Enforce ADR/ADE reporting
 Manufacturers, distributors, hospitals, and research institutions
 Increase awareness regarding cautious and safe use ofTCM
 Healthcare practitioners, herbal practitioners, and the general public

THANKYOU
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)

ACKNOWLEDGMENTS
This 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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