Challenges for Pharmacoepidemiology, Pharmacovigilance and Drug Safety, with a Focus on China

1
Challenges for Pharmacoepidemiology,
Pharmacovigilance and Drug Safety, with a Focus
on China
Shanghai, October 2005

• Chris J. van Boxtel, MD, PhD
• Emeritus Professor of Clinical Pharmacology
• University of Amsterdam
• The Netherlands

2
2
WHO definition of Pharmacovigilance

• The science and activities relating to the
  detection, assessment, understanding and
  prevention of adverse effects or any other
  drug-related problem

3
Aims of Pharmacovigilance

• to improve patient care and safety
• to improve public health and safety
• to contribute to the assessment of benefit, harm,
  effectiveness and risk of medicines
• to promote education and clinical training
• to promote effective communication to the public
• to promote rational and safe use of medicines

3
4
Vice Premier Wu Yi, on behalf of the State
Council, reports on drug safety and its
supervision to the Standing Committee of the
Tenth National People's Congres, June 29, 2005.

• 1. Further implement special rectification
  projects2. Continue the building of two
  networks in rural
  areas3. Rectify and standardize drug
  advertisements4. Try to reduce drug
  prices5. Curb irrational drug use6. Strengthen
  supervision capabilities

4
5
5
6
Pharmacovigilance becomes the more important if
pharmaceutical expenditures are a major part of
total medical expenditures.
6
7
Medical and pharmaceutical expenditures in China
(1995-2003)
(After Xi Sun et al., Chinese Cochrane Centre,
Nov. 2004)
7
8
Surveillance and epidemiology are interrelated
and complementary.
ADR reports alone may suffice for regulatory
decision making under certain circumstances.
ISoP and ISPE discussions, Philadelphia, August
2003 Pharmacoepidemiol Drug Saf 14,
665-667, 2005
8
9
Epidemiologic studies done prior to approval of
the indication for the new drug may provide
information of the expected rates of events.
ISoP and ISPE discussions, Philadelphia, August
2003 Pharmacoepidemiol Drug Saf 14,
665-667, 2005
9
10
Large simple safety trials and structred cohort
studies such as Prescription Event Monitoring
(PEM) can provide relevant risk information.
ISoP and ISPE discussions, Philadelphia, August
2003 Pharmacoepidemiol Drug Saf 14,
665-667, 2005
10
11
Lareb reports to the Dutch regulatory authority,
the Dutch Medicines Evaluation Board
Lareb is the centre for knowledge about adverse
drug reactions in the Netherlands
11
12
12
13
13
14
Core Indicators
14
15
Lareb, a Regionalised organisation
15
16
Regional Coordinators

• South-west Netherlands regional coordinator,
  internist-immunologist
• South-east Netherlands regional coordinator,
  pharmacist
• North-west Netherlands regional coordinator, MD
• North-east Netherlands regional coordinator,
  pharmacist
• Middle Netherlands regional coordinator, MD

16
17
Each year Lareb receives reports of almost 4500
suspicious effects. Of these 20 relate to
serious adverse drug reactions.
17
18
Some Frequently Reported ADRs

• Anafylactic reactions by NSAID's
• Angioedema
• Trombo-embolic complications of use of
  anticonceptives
• Photoreactivity
• Haemolytic anaemia
• Hair loss
• Statins and muscle complaints
• Complaints after substitution
• Systemic effects of corticosteroïds
• Taste disturbances

18
19
Substitutions

• The new product is identical to the product that
  is substituted
• The new product is a parallel imported product
• The new product is a generic and bioequivalent
• The new product is a generic but not
  bioequivalent

19
20
Reporting of Adverse Drug Reactions

• by physicians
• by other health professionals
• pharmacists, nurses
• by patients

20
21
Direct Patient Reporting
21
22

• Degree of Documentation of Patient Reports
• Good 32 (27)
• Average 53 (64)
• Bad 15 (9)

22
23

• Provisional first conclusions
• Acceptable number of reports
• Acceptable quality of reports
• Main motivation doubt whether their health
  professional reports !

23
24
Challenges for Lareb

• Improvement of the quality of the reports
• Better use of pharmacoepidemiologic expertise
• Better integration with academic pharmacology
• Better use of sophisticated (statistical)
  technology
• The evaluation of direct patient reporting

24
25
Pharmacovigilance in industrialized countries

• Considered an essential part of drug regulation
• Well-established systems for more than 25 years
• Regulatory systems - well-developed

25
26
Pharmacovigilance in developing countries

• Easier access to any drug
• Regulation may not be well developed
• Quality issues
• Expired drug
• Still considered a luxury

26
27
27
28
China is the most populous country in the world,
home to 1.3 billion people (20 of the world's
total)
China, with nearly 3.7 million square miles (9.6
million sq km) is the third largest country in
land mass, just slightly larger than USA
28
29
China
7 billion in drug sales in 2001 worlds 9th
largest market Pharmaceutical market has grown
10-15 per year for the last 15 years Domestic
pharmaceuticals occupy approximately 70 of the
market Retail drug outlets expected to grow, but
hospitals are still main distributors of
pharmaceuticals
29
30
Healthcare in China

• 15 of population has health/medical insurance
• 310,000 Medical Health Institutions (gt 13,000
  hospitals)
• 16,000 Distributors/Sub-distributors
• All major multi-national companies present
• Evolution towards Western health problems

30
31
Potentially a very large, world scale ADR database
31
32
The volume of reports for a given drug is
affected by many forces

• Recency of Marketing
• Volume of use
• Publicity (lay press, regulatory and manufacturer
  communication!)
• A good working relationship with potential
  reporters
• Type and severity of the event (professional
  judgement!)

32
33
For the first three years after China joined the
WHO Pharmacovigilance Program in 1998, a total of
900 ADR cases were reported in China. However, at
the same time, the Uppsala Drug Monitoring Centre
has received 150-200 thousands case reports
annually.
(After Xi Sun et al., Chinese Cochrane Centre,
Nov. 2004)
33
34
Products to be Monitored

• New Chemical Entities
• health professional/industry reporting,
  utilisation of information from other regulatory
  agencies
• Vaccines
• public health program managers
• Generics
• prescribers (industry reporting unlikely)
• OTC
• health professionals, consumers
• Traditional Complementary Medicines health
• professionals, consumers, TCM practitioners

34
35
Problem Areas for China

• OTC
• Generics
• Traditional Complementary Medicines
• Counterfeit drugs GMP problems

35
36
Differences between prescription medicines and
OTCs.

• Less healthcare professional input
• Absence of records per se
• Absence of linkage to other medical records
• Direct-to-consumer advertising often allowed
• Inappropriate expectations, demand and use of
• OTC medicines
• Limited opportunity for ongoing patient follow-up
  and monitoring of safety

36
37
Generic prescribing?

• Advantages
• Cost

• Disadvantages
• Quality
• Variability
• Bioinequivalence
• Prescription errors
• Medication errors

37
38
Quality and variability issues

• Dose differences
• Enantiomer ratio differences
• Differences of constituents
• Tablet dissolution rate differences
• Differences in particle size distributions
• Release rate differences

38
39
Dilemmas in bioequivalence testing

• Bioequivalence standards (90 CI 0.8 to 1.25)
• Bioequivalence parameters (AUC, Cmax , Tmax)
• Transitivity of bioequivalence

39
40
Generics often are different

• Packaging
• Color
• Tablet size
• Name
• Coating
• Taste

40
41
Few pharmacovigilance centers are prepared and
capable to differentiate between signals about
products of different manufacturers of generics.
41
42
In Traditional Chinese Medicine (TCM) mostly
herbal medicinal products (HMPs) are used

• HMPs can be toxic and numerous examples of liver,
  kidney and other organ damage are on record

HMPs are not to the same extend submitted to
stringent regulation and control
HMPs can be contaminated or adulterated with
prescription drugs
42
43
Evolution of the Essential Drug List in China
(After Xi Sun et al., Chinese Cochrane Centre,
Nov. 2004)
43
44
Problems in Herbal Pharmacovigilance Common name
Botanical name Chemical
relation

• Chinese, Asian Ginseng Panax ginseng
  Meyer Standard
• American Ginseng Panax quinquefolius L. Similar
• Tienchi Ginseng Panax pseudoginseng
  Wall. Similar
• Siberian Ginseng Eletherococcus Different
• senticosus Maxim.
• Russian Ginseng Acanthopanax Different
• senticosus Harms.
• Brazilian Ginseng Rumex hymenosepalus
  Torr. Different
• Wild red Am. Ginseng Pfaffia paniculata (Mart.)
  Kunze. Different
• Alaskan Ginseng Echinopanax Different
• horridum (Sm.) Decne.)
• Wild Ginseng Aralia nudicaulis L. Different
• Ayurvedic Ginseng Withania somnifera (L.)
  Dunal Different
• Ginseng of the Andes Lepidium meyenii
  Walpers Different

44
45
WHO herbal ADR databaseValid scientific
botanical names

• No internationally standardized and accepted
  classification of all botanical names of
  medicinal herbs exists.
• Therefore the UMC has created a list of preferred
  botanical names and their synonyms.
• The preferred names are...
• ...the complete Latin binomial name including
  the author.
• ...assigned in collaboration with Royal
  Botanical Gardens of Kew, London.
• ...specified with part and extract (in English)
  if given.

45
46
Necessity of the continuous safety monitoring of
herbal medicines

• Limited knowledge about the ingredients
• Limited knowledge about their effects
• Often a lack of stringent quality control
• The heterogenous nature of herbal medicines

46
47
Reporting of ADRs caused by Traditional Chinese
Medicine (TCM)

• ADRs caused by TCM are unrecognized
• The safety of TCM is overestimated
• Sometimes ADRs are misconstrued as part of the
  healing action
• TCM practitioners are less likely to report
• Patients who resort to TCM are more likely to
  believe unscientific claims
• Patients who resort to TCM are less likely to
  report what they suffered

47
48
Differential reporting of ADRs to herbal remedies
and conventional OTCs
From Barnes et al. British Journal of Clinical
Pharmacology 45 (5), 496-500, 1998.
48
49
Region (reports)
Drug categories responsible for the majority of
ADRs
Categories of drugs and rate of ADRs

• Antibacterial (48.2), traditional Chinese
  medicine (13.4)
• Antiinfective (26.2), traditional Chinese
  medicine related (19.8)
• Antibacterial (50.46), cardiovascular drugs
  (25.23)
• Antibacterial (50), biological products (13.04)
  
• Antibiotics (30.5), cardiovascular drugs (21.5)
  

• 119 hospitals in Beijing (6 Years, 5900 pts)
• 1 hospital in Guangzhou, Guangdong
• 4 hospitals in Luoyang, Henan (1year, 107 pts,
  inpatients department of pediatrics)
• 1 hospital in TaiYuan, ShanXi (4 years, 46 pts)
• 1 hospital in ShenYang, LiaoNing (2years, 200
  pts)

(After Xi Sun et al., Chinese Cochrane Centre,
Nov. 2004)
49
50
There is a need for greater awareness that
adverse reactions apparently due to a
conventional medicine, might in reality be due to
a herbal medicine or a drug interaction between a
herbal medicine and a conventional drug,
particularly when a health professional is
unaware of the extent of a patient's
self-medication with alternative therapies.
Woodward KN Hum Exp Toxicol 24, 219-33, 2005.
50
51
The educating of doctors, pharmacists, industry
and patients about drug safety and the importance
of ADR reporting can certainly be be listed among
the greatest challenges.
51