Transcript World Health Organization Quality Problems with Antiretrovirals Dr Mary R. Couper Quality Assurance and Safety: Medicines World Health Organization.

World Health Organization
Quality Problems with
Antiretrovirals
Dr Mary R. Couper
Quality Assurance and Safety: Medicines
World Health Organization
Quality of Medicines
 Good quality medicines are essential to
promote public health - in some African
countries 30-50% of samples tested are of
poor quality
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429 samples from Cameroon, Madagascar,
Chad tested - 18% failed, 16 were counterfeit
175 samples from Tanzania tested - 17% failed
581 samples from Nigeria tested - 48% failed
788 samples tested in Zimbabwe - 17% failed
Quality problems
 Many African countries medicines are sold
in open market places and by street vendors
 Many medicines are smuggled or imported
illegally
 Most domestic manufacturers do not meet
Good Manufacturing Practices
 Storage and distribution conditions are
inappropriate
 Corruption is a serious problem
About 50% of the countries in sub-Saharan Africa have very
limited/no capacity to control the market-where regulatory
authorities exist enforcement is weak
50%
48.0%
42.0%
45%
40%
35%
30%
25%
20%
10%
15%
10%
5%
0%
V. limited capacity
Basic capacity
Moderate capacity
Antiretrovirals on WHO’s Essential
Drug List
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Nucleoside reverse transcript inhibitors
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didanosine (ddl)
lamivudine (3TC)
stavudine (d4T)
zidovudine (ZDV or AZT)
Non-nucleoside reverse transcriptase inhibitors
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efavirenz (EFV or EFZ)
nevirapine (NVP)
Protease inhibitors
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indinavir (IDV)
lopinavir + ritonavir (LPV/r)
nelfinavir (NFV)
ritonavir ( r )
saquinavir (SQV)
Quality concerns
 Partners in the '3x5' strategy, such as WHO,
UNAIDS, and many other UN organizations
are involved in the procurement of
antiretrovirals drugs.
 The supply of antiretroviral products that
are effective and of acceptable quality has
become a major concern at both
international and country level.
Prequalification scheme
 Why was the launch considered?
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Countries and other interested parties asking
WHO to initiate pre-qualification of essential
drugs referring to positive experience of
vaccines pre-qualification
Increasing pressures to increase access to
antiretrovirals owing to epidemic
Prequalification of HIV/AIDS Drugs
- UN joint activity
 Partners
 UNAIDS; UNICEF; UNFPA; WHO
 With the support of World Bank
 WHO role
 Technical assistance based on WHO norms
and standards, plus ICH and other standards,
where applicable
Activities of Prequalification
Scheme
 Assessment of dossiers: teams of
professionals from national drug regulatory
authorities:: Including Canada, Denmark, Estonia, Finland,
France, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa,
Sweden and Zimbabwe
 Manufacturing site inspections: teamwork
of inspectors: WHO representative (qualified GMP inspector),
inspector from well-established inspectorate (Pharmaceutical Inspection
Cooperation Scheme countries) and inspector(s) from national drug
Regulatory authorities
Basic principles
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Voluntary for participating manufacturers
Legitimate - General procedure and standards
approved through WHO Expert Committee
Widely discussed in many fora
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FIP Congress, Nice 2002
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Supported by ICDRA in 2002 and 2004,
 Transparent (all information available on the
web site http://www.who.int/medicines/)
 Open to both innovators and
multisource/generic manufacturers
 No cost for applicants during pilot phase
General procedure
Steps of the Procedure
1. Invitation for Expression of Interest
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Wide publication
Open, transparent
Specify products required
2. Guidelines for product dossier
compilation and requirements available
1. Multi-source products
2. Innovator products
3. Receiving of dossiers
General procedure (cont.)
4. Screening of dossiers
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Screen for completeness
Inform supplier
Listed for a possible site inspection
5. Dossier evaluation
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Team of experts (quality, pharmaceutical
development, bio-equivalence etc) from
national regulatory authorities
Standard: Including, but not limited to WHO
Manual and guidelines
Outcome of the evaluation communicated to
supplier
General procedure (cont.)
6. Site inspection
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WHO GMP
Inspection team:
- Appointed inspector preferably from DRA
- Local, national inspectorate
- WHO representative
7. Report and outcome
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Reports on dossier evaluation and site
inspection- communicated to
supplier/manufacturer
Compliance? Additional information to be
submitted?
Current status
 Good news
 Relatively large number of ARV products
and suppliers indicated
 Many potential suppliers appreciating
feedback and willing to improve
 Unique knowledge obtained about generic
ARVs “Quality” generic products do
exist
Current status
 Bad news
 Only limited number of products have met the
required standards
 5 antiretrovirals recently removed from list
 Takes time to get into compliance
• Data to be generated, tests carried out
• GMP upgrade needed
 Bad quality generics may undermine the public
confidence in generics
 Quality Assurance at a price!
http://http://mednet3.who.int/prequal/
Quality cannot be assessed, tested or inspected into
the product. It has to be built into it.
Problem: Counterfeiting medicines is
a major public health concern
WHO Definition of a counterfeit medicine
 A product that is deliberately and fraudulently
mis-labelled with respect to source and/or
identity. Counterfeiting can apply to both
generic and branded products. Counterfeit
products may include:
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products with the correct ingredients
with the wrong ingredients
without ingredients
with incorrect quantities of active ingredients
with fake packaging
WHO has been receiving reports on cases
of counterfeit drugs since 1982
 About 70% of the cases were reported by developing
countries
 Less than 30% came from developed countries
 Countries that have sent reports: less than 10-15% of
WHO Member States
 Majority of the reports received do not make distinction
between substandard and counterfeit drugs
 Most cases have not been validated or confirmed
 The sources of the counterfeit drugs are unknown
Counterfeiting: increasingly sophisticated
business
What is the problem?
 Counterfeiting medicines is a lucrative
"business" and seems emerging, affecting
both developing and developed countries
 The real magnitude of the problem is
unknown:
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Existing data not comprehensive
All parties concerned reluctant to make data
AVAILABLE or REPORT
Types of counterfeits reported to WHO included
the following
Poor quality
24%
wrong
ingredient
7%
Wrong
packaging
5%
Low content
21%
No active
ingredient
43%
Example of counterfeit: Ginovir 3D
Information Exchange System
Alert No. 110
Counterfeit triple antiretroviral
combination product (Ginovir 3D)
zidovudine (200 mg), lamivudine (150 mg)
and indinavir (40 mg).
detected in Côte d’Ivoire
Recommendation from 11th ICDRA
 WHO, in collaboration with other
stakeholders, should develop a
INTERNATIONAL CONVENTION
ON COUNTERFEIT DRUGS.
Before the next ICDRA, WHO should
convene a meeting of national
regulatory authorities to discuss further
the concept paper and related issues.
Why international convention?
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National measures insufficient
a. regulation
b. political will and public health policy
c. criminal law and sanctions
d. cooperation
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Trade in counterfeit drugs is global
Preamble, Objective(s), Principles and
Definitions
1. Formulate coordinated approach to prevent and
combat counterfeit drugs
2. Create a basic duty
3. Promote basic cooperation
4. Identify possible words to define: counterfeit
medicine, medicine etc.
5. Establish and structure international cooperation
...
Conclusions
 Fighting counterfeit medicines
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Working together is the key
The question remains how best to
achieve it?