November 1, 2002
The draft version of this document, first posted in August 1999, was based on a DAVDP advisory committee meeting, convened in July 1997, to discuss the use of HIV RNA endpoints for traditional approval of antiretroviral drugs. This document has been updated to address public comments to the draft version and to include pertinent information from a DAVDP advisory committee meeting, convened in January 2001, to address issues relating to trial design in heavily treatment experienced HIV-infected patients.
This guidance does not address specific phase-1 and phase-2 development issues, development of alternate dosing regimens, or the use of HIV-1 resistance testing. These issues will be addressed separately in future guidance documents.
In addition to consulting guidance documents, sponsors are encouraged to contact the division to discuss specific issues that arise during the development of an antiretroviral drug product.
Accelerated approvals of antiretroviral drugs have been based for years on changes in surrogate endpoints, such as CD4 cell counts and plasma HIV RNA levels. Traditional approvals were based on clinical endpoint trials assessing the effects of a drug on mortality and/or HIV disease progression. With the availability of potent antiretroviral drug regimens and sensitive assays for assessing plasma HIV RNA, the standards of clinical practice evolved to a paradigm emphasizing maximal and durable HIV RNA suppression. In addition, with the successes of combination therapy and the subsequent decline of HIV-related illnesses (Palella et al., 1998; Hogg et al., 1999), it became clear that a requirement for clinical endpoint studies for every traditional approval was no longer necessary nor feasible.
In July 1997, the Agency convened an advisory committee meeting to consider the use of changes in HIV RNA levels as endpoints in clinical trials supporting traditional approval of antiretrovirals. To evaluate the feasibility of using HIV RNA levels as a study endpoint, a collaborative group of pharmaceutical, academic, and government scientists investigated relationships between treatment-induced changes in HIV RNA and clinical endpoints from ongoing and completed antiretroviral trials (Murray et al., 1999; Hill et al., 1998). In several analyses of more than 5000 patients in multiple trials, a clear association was identified between initial decreases in plasma HIV RNA levels and reduction in the risk of clinical progression and death. This relationship was observed across a range of patient characteristics including pretreatment CD4 counts and HIV RNA levels, prior drug experience, and treatment regimen. Based on these data, the Division of Antiviral Drug Products advisory committee concurred that treatment-induced decreases in HIV RNA levels were highly predictive of meaningful clinical benefit and that HIV RNA measurements could serve as endpoints in trials designed to support both accelerated and traditional approvals. The Division proposed that accelerated approvals could be based on studies that show a drugÕs contribution toward shorter-term reductions in HIV RNA (e.g., 24 weeks) while traditional approvals could be based on trials that show a drugÕs contribution toward durability of HIV RNA suppression (e.g., for at least 48 weeks). The committee agreed with this proposal and also recommended that changes in CD4 cell counts be consistent with observed HIV RNA changes when considering approval of an antiretroviral drug.
The guidance document can be accessed here.