Prequalification Update - 19 November 2004

HETERO DRUGS LTD WITHDRAWS ANTIRETROVIRALS FROM WHO PREQUALIFICATION LIST FOR FURTHER REVIEW

WHO Geneva.

Following an inspection by the World Health Organization (WHO), generic manufacturer Hetero Drugs Limited, in Hyderbad, India, is withdrawing six antiretrovirals* from the WHO prequalification list in order to review data on their bioequivalence. The company has told WHO it recognized that the "centres" it had used for studies of bioequivalence "were incompatible with the current standards" and that there were "deficiencies in the data submitted … for the studies done at these centres."

As in the case of Ranbaxy last week, the company evaluated the contract research organizations (CROs) it had used 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 and Good Laboratory Practice. Hetero Drugs has committed to contract different CROs and submit new test results for the bioequivalence of the six medicines as soon as possible. "Our findings, and the companies' admission of responsibility by withdrawing their products, show that CRO inspections are necessary," said Dr Lembit Rago, Coordinator of Quality, Safety and Efficacy of Medicines at WHO. "Current WHO procedures are ultimately improving medicines monitoring mechanisms which will, in the long term, ensure better quality treatment for patients."

Ongoing WHO inspections of CROs conducting tests on antiretrovirals are part of the continuing monitoring process and an integral component of the prequalification work. That work reflects WHO's responsibility to assist countries in promoting quality medicines and improving their quality assurance mechanisms. 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. Bioequivalence tests are conducted in volunteers whose blood is tested after receiving treatment with the medicine, to determine whether the blood concentration of the generic drug is similar to that of the originator product. The current WHO list of prequalified medicines contains 48 antiretrovirals, including a triple fixed dose combination (a three-in-one pill) manufactured by Cipla. WHO's advice to countries is that, 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 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.