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

2. 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 l 429 samples from Cameroon, Madagascar, Chad tested - 18% failed, 16 were counterfeit l 175 samples from Tanzania tested - 17% failed 581 samples from Nigeria tested - 48% failed l 788 samples tested in Zimbabwe - 17% failed

3. 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

4. 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

5. Antiretrovirals on WHO’s Essential Drug List §Nucleoside reverse transcript inhibitors l didanosine (ddl) l lamivudine (3TC) l stavudine (d4T) l zidovudine (ZDV or AZT) §Non-nucleoside reverse transcriptase inhibitors l efavirenz (EFV or EFZ) l nevirapine (NVP) §Protease inhibitors l indinavir (IDV) l lopinavir + ritonavir (LPV/r) l nelfinavir (NFV) l ritonavir ( r ) l saquinavir (SQV)

6. 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.

7. Prequalification scheme §Why was the launch considered? l Countries and other interested parties asking WHO to initiate pre-qualification of essential drugs referring to positive experience of vaccines pre-qualification l Increasing pressures to increase access to antiretrovirals owing to epidemic

8. Prequalification of HIV/AIDS Drugs - UN joint activity lPartners l UNAIDS; UNICEF; UNFPA; WHO l With the support of World Bank lWHO role l Technical assistance based on WHO norms and standards, plus ICH and other standards, where applicable

9. 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

10. Basic principles §Voluntary for participating manufacturers §Legitimate - General procedure and standards approved through WHO Expert Committee Widely discussed in many fora l FIP Congress, Nice 2002 l 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

11. 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

12. General procedure (cont.) 4. Screening of dossiers l Screen for completeness l Inform supplier l Listed for a possible site inspection 5. Dossier evaluation l Team of experts (quality, pharmaceutical development, bio-equivalence etc) from national regulatory authorities l Standard: Including, but not limited to WHO Manual and guidelines l Outcome of the evaluation communicated to supplier

13. General procedure (cont.) 6. Site inspection l WHO GMP l Inspection team: -Appointed inspector preferably from DRA -Local, national inspectorate -WHO representative 7. Report and outcome l Reports on dossier evaluation and site inspection- communicated to supplier/manufacturer l Compliance? Additional information to be submitted?

14. Current status §Good news l Relatively large number of ARV products and suppliers indicated l Many potential suppliers appreciating feedback and willing to improve l Unique knowledge obtained about generic ARVs “Quality” generic products do exist

15. Current status §Bad news l Only limited number of products have met the required standards l 5 antiretrovirals recently removed from list l Takes time to get into compliance Data to be generated, tests carried out GMP upgrade needed l Bad quality generics may undermine the public confidence in generics l Quality Assurance at a price!

16. http://http://mednet3.who.int/prequal/ Quality cannot be assessed, tested or inspected into the product. It has to be built into it.

17. Problem: Counterfeiting medicines is a major public health concern

18. 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: l products with the correct ingredients l with the wrong ingredients l without ingredients l with incorrect quantities of active ingredients l with fake packaging

19. 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

20. Counterfeiting: increasingly sophisticated business

21. 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: l Existing data not comprehensive l All parties concerned reluctant to make data AVAILABLE or REPORT

22. Types of counterfeits reported to WHO included the following

23. 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

25. Recommendation from 11 th 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.

26. 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 globa l

27. 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...

28. Conclusions §Fighting counterfeit medicines l Working together is the key l The question remains how best to achieve it?