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?