MSF Briefing Note: Two Cipla AIDS Drugs Removed from WHO Prequalification List

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Briefing Note, June 16th 2004. Médecins Sans Frontières / Campaign

for Access to Essential Medicines

Two Cipla AIDS Drugs Removed from WHO Prequalification List

In 2001, the United Nations started a pilot project to assess the

quality of malaria, TB and HIV/AIDS pharmaceutical products that the

UN agencies (WHO, UNICEF, UNFPA and UNAIDS, supported by the World

Bank) purchase. Managed by the World Health Organization, the

Prequalification Project assesses essential medicines and their

production sites worldwide based on dossiers submitted by drug

manufacturers.

The WHO Prequalification Project has so far assessed more than 90

drugs, over half of these generics. The existence of an international

system of prequalified products has dramatically increased access to

essential medicines, particularly antiretroviral drugs, in developing

countries. The list is updated regularly and it provides vital

guidance for governments in procuring essential drugs which meet

internationally-agreed quality standards.

On May 27th 2004, the WHO removed two products from its

prequalification list. The products are two antiretroviral medicines

manufactured by the Indian company Cipla: lamivudine (3TC) 150 mg

tablet (LAMIVIR®), and the fixed dose combination lamivudine (3TC)

150mg/zidovudine (AZT) 300mg tablet (DUOVIR®)(1)

How could products have been prequalified and later withdrawn from

the list?

The WHO prequalification project is an ongoing process that includes

periodic inspections of production sites and pharmaceutical company

sub-contractors.

These two products were taken off the list because of questions

concerning a bioequivalence study, one element of the dossier

submitted to WHO by Cipla. As is standard practice in the industry,

Cipla commissioned a Contract Research Organization (CRO) to conduct

the bioequivalence studies for these products in 2001.

Initially, the studies conducted by this CRO were accepted by WHO,

based on documentation submitted. However, a recent inspection by WHO

of the CRO showed that there were deficiencies at this organization

and, as a result, previously accepted studies and data are now

considered inadequate.

Therefore the two products have been removed from the

prequalification list. (2)

WHO has informed Cipla and the CRO of the outcome of the inspection.

If Cipla submits new data, these will be assessed and the products

could be again considered for inclusion on the prequalification list,

if the data are found acceptable.

The manufacturing sites and the quality of these two products are not

being questioned by the WHO. Rather, in the recent inspection, the

CRO that conducted the bioequivalence studies was found to have

failed to meet international standards, leading to lack of proof of

therapeutic equivalence.

MSF supports the WHO Prequalification Project and believes that

ongoing monitoring by the WHO is a sign of an efficient process. The

rigour of this process ensures that companies are always striving to

improve their assessment of quality.

Cipla communications

Cipla has informed MSF that if countries or organizations prefer to

return these two products rather than continue using them, Cipla will

offer full refunds. Cipla has also confirmed it has already began new

bioequivalence studies on the two products and that these studies

will be completed by the end of July.

MSF's response

MSF's first priority is to ensure that no patients in our programmes

face treatment interruption. MSF also recognizes that the ultimate

authority for decisions on the use of drugs rests with a country's

national drug regulatory authority (NDRA).

Considering these two points, MSF has decided to put supplies of

these two Cipla drugs on hold until the results of new bioequivalency

studies are available and are reviewed by the WHO Prequalification

Project.

In general, MSF will seek to substitute other prequalified drugs for

the two Cipla drugs, but the use of these two products will be

decided on a case-by-case basis taking into consideration the

decisions of NDRAs and availability of alternatives.

Since the vast majority of MSF's patients are on triple fixed-dose

combinations, they will not be affected.

1) The WHO decision does not affect Cipla's triple fixed-dose

combination nevirapine/lamivudine/stavudine (TRIOMUNE), which is

still on the prequalification list, or any other Cipla products.

2) The WHO has posted the following explanation on their website (May

27th 2004):

" [the two products were] Removed from the list as a result of the

outcome of an inspection performed by the World Health Organization

(WHO) in which compliance with Good Clinical Practices (GCP) and Good

Laboratory Practices (GLP) was assessed, as well as data verification

of the bioequivalence study at the Contract Research Organization

(CRO) used by the sponsor. Products are subject to re-assessment when

completely new data set is presented about the bioequivalence

studies. "

_________________________

M. Cohen

U.S. Director, Campaign for Access to Essential Medicines

Doctors Without Borders/Médecins Sans Frontières (MSF)

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