Generic ARVs and WHO prequalification list

Polly Clayden, HIV i-Base

Ranbaxy and Hetero withdraw antiretrovirals from WHO prequalified list

On 9 November WHO announced that Ranbaxy Laboratories had voluntarily withdrawn all its antiretrovirals from WHO prequalification. Three other Ranbaxy drugs were removed from the list earlier this year following findings of serious discrepancies in results from bioequivalence studies presented to WHO after inspections at the Contract Research Organisations (CROs) that conducted these tests.

A further announcement was made on 19 November that following an inspection by WHO, Hetero would withdraw six antiretrovirals from the list in order to review their bioequivalence data. Similar to Ranbaxy, Hetero evaluated the CROs it had used to conduct the studies, after receiving a warning letter sent by WHO to all manufacturers earlier this year, and found them non-compliant with international standards of Good Clinical Practice (GCP) and Good Laboratory Practice (GLP).

Ranbaxy have presented WHO with a plan with proposed dates for the submission of new data for their products. The WHO statement says the first study is expected to be completed by December 2004. Likewise, Hetero will contract different CROs and submit new test results for the bioequivalence of the drugs “as soon as possible”.

The WHO statement explains: “The irregularities found during the CRO inspections do not undermine the proven pharmaceutical quality of the medicines — including their purity and stability — but show that not all CROs can be relied upon as a source of evidence on the medicines’ bioequivalence with their originator products.”

They advise countries: “ In principle, patients should suspend the use of de-listed medicines and switch to other prequalified products. However, if it is difficult to obtain alternative prequalified products immediately, it is recommended that patients continue the use of de-listed products. The risk of withholding treatment is higher than that of providing medicines whose bioequivalence is not proven but which have demonstrated quality and safety. A switch to non-prequalified products is not recommended, as their quality has not been documented by WHO.”

The seven Ranbaxy products are: indinavir 400 mg capsule, blister (60, 100); lamivudine 150 mg tablet, blister (60, 100); lamivudine/stavudine 150 mg/40 mg tablet, Al strip (10), 60 in box; lamivudine/stavudine 150 mg/30 mg tablet, Al strip (10), 60 in box; nevirapine 200 mg tablet, blister (60, 100); stavudine 30 mg capsule, Al strip (10), 60 in box; zidovudine 300 mg tablet, blister (60, 100).

The Hetero products withdrawn are: stavudine 40 mg capsule; stavudine 30 mg capsule; lamivudine 150 mg plus zidovudine 300 mg tablet; indinavir 400 mg capsule; lamivudine 150 mg tablet; zidovudine 300 mg tablet.

And two Cipla antiretrovirals return to the WHO list…

Then on the 30 November 2004 WHO announced that it was reinstating two antiretrovirals manufactured by Cipla, in its list of prequalified medicines. The two medicines had been dropped form the list by WHO since May this year again due to non-compliance with international standards at CROs used by Cipla to conduct bioequivalence studies on the products.

Following the delisting, new bioequivalence studies were performed and further WHO scientific assessment and inspections have validated the results of these new studies, including the CROs involved, with all international requirements.

The two Cipla drugs are: lamivudine 150mg tablet, blister pack of 10; and lamivudine 150mg plus zidovudine 300mg tablet, blister pack of 10

On the WHO website – information and guidance for regulatory bodies, national AIDS programmes, doctors:


In a Lancet editorial on November 20 the authors write: “So the latest news of the withdrawal of much-needed antiretrovirals from the prequalification list is both bad and good. Bad, obviously, for the patients and health carers affected locally. But good news because it shows that this little known part of WHO is effective and has teeth that can bite rapidly. QSM [Quality Assurance and Safety: Medicines] is a small team at WHO’s headquarters that knows the importance of training local drug regulatory authorities, and has the ability to use international inspectors in local sites. And prequalification status means that some of the most important drugs are being made safely available in parts of the world where they are most needed.” [1]

We would add that the process of reinstatement has been such a long one – the reinstated Cipla products were delisted in May – and the first delisted Ranbaxy products are not anticipated to be back until the spring.

Although not mentioned in the WHO statements, the generic companies are also seeking approval for their drugs from the FDA; Gregg Gonsalves from GMHC in New York raised (yet more) troubling issues of US unilateralism in an address to last months Glasgow conference: “The US is driving countries to use brand name drugs, the Administration and its surrogates such as the Hudson Institute and Public Interest Watch have waged a successful campaign to undermine faith in the safety and effectiveness of generic ARVs. While there have been real issues about some of the bioequivalence studies of generic ARVs over the past few months, the US is using this to undermine countries’ trust in the WHO on a more general level, implying that the WHO’s entire system of evaluating ARVs in suspect. In fact, the US has set itself up to be the worldwide drug regulatory body and will evaluate generic ARVs through the US Food and Drug Administration, making itself the gatekeeper for the global community on which drugs do and do not get used widely across the world. In fact, Ranbaxy, a leading generic ARV maker has pulled all its drugs from the WHO evaluation process and is submitting its compounds for approval by the US FDA. Let’s see how fast Ranbaxy’s drugs are approved by the USFDA and how much of the market the company will lose as it waits for the blessing of the US government.” [2]


  1. The important world of drug prequalification.Lancet, Volume 364, Number 9448     20 November 2004
  2. Gonsalves G, Obstacles to 3×5: Speech to 7th International Congress on Drug Therapy in HIV Infection Glasgow 2004.

Links to other websites are current at date of posting but not maintained.