Removal of Antiretroviral Products from the WHO List of Prequalified Medicines

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


PRACTICAL IMPLICATIONS

For National Drug Regulatory Authorities

Additional explanation

The five products have been removed because proof of bioequivalence is missing as a result of non-compliance with good clinical and laboratory practices. However, they do meet other quality specifications, such as the active pharmaceutical ingredient purity, stability, and manufacture in compliance with Good Manufacturing Practices in a state-of-the-art pharmaceutical plant.

Recommended action

Many national drug regulatory authorities do not require bioequivalence data to admit generic drugs into their markets. In this case there is no legal obligation to withdraw marketing authorization for the five drugs that were removed. In countries where bioequivalence is required, the national drug regulatory authority should consider one or more of the following actions:

  • Request a confidential copy of the inspection report(s) from WHO;

  • Temporarily waive its requirement of bioequivalence for these products as an emergency measure, requesting that the manufactures submit data on new bioequivalence studies within four months (if these deadlines are not met, consider withdrawing marketing authorization);

  • Do not release the products in stock for use until further evidence from new bioequivalence studies becomes available;

  • Withdraw marketing authorization for the products;

  • Provide detailed information and advice to programme managers, prescribers and patients on the best ways to manage the situation without compromising the goals of treatment programmes.

PRACTICAL IMPLICATIONS FOR PROGRAMME MANAGERS

Additional explanation

In countries where bioequivalence data are not required by the national drug regulatory authority there is no legal need to withdraw the products; and even in countries where these data are required, the authorities may (temporarily) decide not to withdraw them (see above). In all cases, a careful balance must be sought between the risks associated with the lack of proof of bioequivalence in these products and the individual and public health risk of interrupting treatment should no alternative medicines be found.

In general, switching to similar antiretrovirals (ARVs) from alternative, prequalified suppliers would be the most appropriate response, if and when such products are available. (see Annex 1 below) However, switching to non-prequalified ARVs is not advised since not only has their bioequivalence not been confirmed, but, in addition, other quality aspects have not been verified by WHO.

Recommended action

  • Consult with the national drug regulatory authority to establish the best course of action.

  • Prepare and implement a communication strategy addressed to prescribers and patients.

  • Take the necessary measures to switch to alternative prequalified products (listed in Annex 1 below). In this regard, the following actions are recommended in specific situations:

  • (a) The procurement of de-listed drugs is considered, but they have not yet been ordered. De-listed products should not be ordered. Instead, other prequalified products should be ordered unless the de-listed medicines are reinstated on WHO’s list of prequalified products.

  • (b) De-listed drugs have been ordered to continue or scale up treatment programmes. De-listed drugs that have been ordered, but not received, should not be accepted. In this case, alternative prequalified products should be ordered instead. However, if alternative suppliers are not immediately available and the non-acceptance of the ordered products could lead to an inability to continue or to start treating patients, the risk of withholding treatment is higher than that of providing medicines whose bioequivalence is not proven but which have, otherwise, been prequalified. In this case it would be justified to accept and use the de-listed products. For follow-up orders, only prequalified products should be used.

PRACTICAL IMPLICATIONS FOR PRESCRIBERS AND PATIENTS

In principle, patients should discontinue using de-listed medicines and switch to other prequalified products (see Annex 1). However, in many cases it will be difficult to find alternative prequalified products immediately. In this situation it is recommended that patients continue to use de-listed products, as the risk of interrupting treatment is higher than that of taking medicines whose bioequivalence is not proven but which have otherwise been prequalified. A switch to non-prequalified products is not recommended as their quality has not been documented by WHO.

The patient should be informed that there is no reason to believe continued use of the de-listed products is dangerous, and that suspending the treatment or switching to alternative ARVs whose quality has not been assured is far riskier.

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