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Quality Problems with Antiretrovirals
Dr Mary R. CouperQuality Assurance and Safety: Medicines
World Health Organization
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 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 vendorsMany medicines are smuggled or imported
illegallyMost domestic manufacturers do not meet
Good Manufacturing PracticesStorage and distribution conditions are
inappropriateCorruption 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
48.0% 42.0%
10%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
V. limited capacity Basic capacity Moderate capacity
Antiretrovirals on WHO’s Essential Drug List Nucleoside reverse transcript inhibitors
didanosine (ddl) lamivudine (3TC) stavudine (d4T) zidovudine (ZDV or AZT)
Non-nucleoside reverse transcriptase inhibitors efavirenz (EFV or EFZ) nevirapine (NVP)
Protease inhibitors 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? 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 Voluntary for participating manufacturers Legitimate - General procedure and standards approved
through WHO Expert Committee Widely discussed in many fora
FIP Congress, Nice 2002 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- 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
Screen for completeness Inform supplier Listed for a possible site inspection
5. Dossier evaluation 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
WHO GMP Inspection team:
- Appointed inspector preferably from DRA
- Local, national inspectorate
- WHO representative
7. Report and outcome 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:
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: Existing data not comprehensive All parties concerned reluctant to make data
AVAILABLE or REPORT
Types of counterfeits reported to WHO included the following
Poor quality24%
wrong ingredient
7% Low content21%
No active ingredient
43%
Wrong packaging
5%
Example of counterfeit: Ginovir 3D
Information Exchange SystemAlert 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?
National measures insufficient
a. regulation
b. political will and public health policy
c. criminal law and sanctions
d. cooperation
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
Working together is the key
The question remains how best to achieve it?