Removal of Antiretroviral Products from the WHO List of Prequalified Medicines

Information and Guidance for Regulatory Bodies, National AIDS Programmes, Doctors and Patients

Department of Essential Drugs and Medicines Policy
Department of HIV/AIDS

1 September 2004¦ WHO continues to receive many questions on the recent de-listing of five medicines from its list of prequalified products. Given the importance of these medicines for patients and for international efforts to scale up treatment, WHO offers below some clearer explanations for the decision to delist the products concerned, and advice for regulatory bodies, national AIDS programme managers, prescribers and patients on what can be done as a response to this at country level.

WHAT HAS HAPPENED?

In May and July 2004, WHO ran a series of inspections of contract research organizations and/or laboratories (hereafter: CROs) as part of its ongoing monitoring of prequalified medicines. The CROs had been contracted by manufacturers to carry out tests to prove the bioequivalence of medicines submitted for prequalification, in accordance with WHO requirements. Bioequivalence tests are clinical trials conducted in healthy volunteers to find out if the concentration of a generic medicine in the blood of a patient is equivalent to that of the originator product. Originally, the data (results) presented to WHO by the manufacturers did prove bioequivalence.

During the inspections, one CRO was found to be compliant with international guidance on Good Clinical Practice and Good Laboratory Practice in doing these studies. However, two other CROs were not found compliant because of serious discrepancies between the original results compiled by the CROs and the results presented to WHO by the manufacturers.

1. Confirmation of two AIDS medicines’ bioequivalence

The CRO which had conducted bioequivalence studies for a triple fixed-dose combination in two different strengths was found compliant. These products (one prequalified in December 2003, the other at the same time as the CRO inspection) are therefore proven to be bioequivalent and can be used as alternatives to two of the recently removed medicines. These are:

  • lamivudine 150mg plus stavudine 40 mg and nevirapine 200 mg tablet (Cipla)
    already on the list

  • lamivudine 150mg plus stavudine 30 mg and nevirapine 200 mg tablet (Cipla)
    recently added

2. Five HIV/AIDS medicines were removed from the list for lack of proof of bioequivalence

For five medicines, WHO could no longer accept the report on the bioequivalence studies provided by the manufacturers. Since proof of bioequivalence is a condition for prequalification, and in view of the serious nature of the CROs’ non-compliance, two of the products concerned were removed from the list on 27 May and three others on 4 August. The five products are:

  • Lamivudine 150mg plus stavudine 30mg and nevirapine 200mg tablet (Ranbaxy Laboratories Ltd, Dewas, India, Al strip of 10 or 60 in box)

  • Lamivudine 150mg plus stavudine 40mg and nevirapine 200mg tablet (Ranbaxy Laboratories Ltd, Dewas, India, Al strip of 10 or 60 in box)

  • Lamivudine 150mg plus zidovudine 300mg tablet (Ranbaxy Laboratories Ltd, Dewas, India, Blister pack of 60 or 100)

  • Lamivudine 150mg tablet (Cipla Ltd, Kurkumbh, India, blister pack of 10)

  • Lamivudine 150mg plus zidovudine 300mg tablet (Cipla Ltd, Vikhroli, India, blister pack of 10).

WHAT DOES THE REMOVAL OF THE FIVE MEDICINES MEAN?

WHO is not a supranational regulatory authority. The list of WHO prequalified products includes medicines which have been evaluated and approved for procurement by United Nations organizations. That list does not have any legal status at national level. In countries, the full responsibility for authorizing marketing and use of medicinal products in public health programmes rests with the national drug regulatory authority. The standards used by WHO for prequalification are more stringent than those applied by many countries. For example, not all countries legally require in vivo bioequivalence studies (small clinical trials conducted in healthy volunteers) for generic drugs; nor do they have stringent requirements for the quality of active pharmaceutical ingredients.

When deciding on the best course of action, national authorities, programmes, prescribers and patients should take the following considerations into account:

  • These products may or may not be bioequivalent;

  • Interruption of ARV treatment constitutes a serious risk for the individual and may have negative implications from a public health perspective.

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