FDA Notifications

New guidance assists HIV drug development

Changes affect approvals for antiretroviral drugs

The Food and Drug Administration (FDA) has issued new guidance intended to assist sponsors in the clinical development of drugs for the treatment of HIV infection. Specifically, it addresses the FDA’s current thinking regarding designs of clinical trials that use HIV ribonucleic acid (RNA) measurements to support accelerated and traditional approvals of antiretroviral drug products. It also is intended to serve as a focus for continued discussions among the Division of Antiviral Drug Products (DAVDP), pharmaceutical sponsors, the academic community, and the public. The draft version of this document, first posted in August 1999, was based on a 1997 DAVDP advisory committee meeting to discuss the use of HIV RNA endpoints for traditional approval of antiretro- viral drugs. This document has been updated to address public comments to the draft version and to include pertinent information from a 2001 DAVDP advisory committee meeting 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. Sponsors should 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. 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 neither necessary or 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 5,000 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 basing accelerated approvals on studies that show a drug’s contribution toward shorter-term reductions in HIV RNA (e.g., 24 weeks) while traditional approvals could be based on trials that show a drug’s contribution toward durability of HIV RNA suppression (e.g., for at least 48 weeks). The committee agreed and recommended that changes in CD4 cell counts be consistent with observed HIV RNA changes when considering approval of an antiretroviral drug.

To access the guidance document, go to the FDA web site at: www.fda.gov/cder/guidance/3647fnl.pdf.