FDA Finalizes HIV Drug Development Guidance

Regulatory NewsRegulatory News | 02 November 2015 |  By 

The US Food and Drug Administration (FDA) has added more detailed definitions for treatment-naïve and treatment-experienced HIV patients and provides recommendations for designing switch trials, according to guidance finalized Monday.

The agency hopes the guidance will "promote and facilitate more drug development in the heavily treatment-experienced population," an FDA spokesman told Focus, by introducing a trial design using "an endpoint of virologic efficacy within 2 weeks or less of randomization."

The new guidance also encourages sponsors to seek traditional approval for new antiretroviral drugs to treat HIV based on long-standing surrogate endpoints and replaces FDA's 2002 guidance Antiretroviral Drugs Using Plasma HIV-RNA Measurements – Clinical Considerations for Accelerated and Traditional Approval.


In the mid-90s, after the "success of combination therapy [and] subsequent decline of HIV-related illnesses," FDA says "it became clear that a requirement for clinical endpoint trials for every traditional approval was no longer feasible."

Between 1996 and 1997, a group of experts "investigated the relationships between treatment-induced changes in HIV-RNA levels and clinical endpoints." After analyzing results from multiple trials, the group "identified a relationship between initial decreases in plasma HIV-RNA levels and reduction in the risk of clinical progression and death."

In 1997, FDA's Antiviral Drug Advisory Committee validated HIV-RNA levels as an endpoint for both traditional and accelerated approvals for HIV treatments. Based on its analysis, the committee said that reductions in HIV-RNA levels over a short period could be used to support accelerated approvals, while longer term reductions could be used to support traditional approval.

New Guidance

Now that HIV-RNA levels have long been validated as an endpoint, FDA says companies should no longer seek accelerated approval, followed by traditional approval later on, saying that "full approval based on an endpoint of HIV-RNA suppression … is the anticipated pathway for marketing approval."

In updating the guidance from its draft form, FDA has further clarified its definitions of the three patient groups.

Treatment Groups

Group 1Fully susceptible to all approved drugs, treatment-naïve or previous treatment with a well-documented treatment history demonstrating no virologic failure.
Group 2Drug resistance to multiple drugs and multiple drug classes and unable to construct a regimen that suppresses HIV-RNA to below assay quantification limits.
Group 3Drug resistance present and able to construct a regimen that suppresses HIV-RNA below assay quantification limits.

The finalized guidance also lays out FDA's expectations for designing switch trials, or trials where patients who are already suppressed on one treatment are changed to a new treatment regimen.

For these trials, FDA says companies should use "the proportion of patients with HIV-RNA greater than or equal to the lower limit of quantification at 48 weeks" as an endpoint. The agency says this approach "differs from the endpoints in Group 1 to 3 trials in that the endpoint focuses on and is powered for virologic failure and not success … because in Switch trials patients are starting with HIV-RNA levels that are already suppressed below the assay limit of quantification."




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