FDA Issues HIV Treatment Final Draft Guidance

Guidance addresses the development of clinical trials to test novel antiretroviral drugs for the treatment of HIV.

The first final guidance in over 13 years for the development of new antiretroviral drugs for the human immunodeficiency virus (HIV) has been released by the US Food and Drug Administration (FDA).

The final guidance, titled Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment, replaces the draft guidance under the same name that was issued in June 2013.

It also takes the place of the final guidance issued in October 2002, titled Antiretroviral Drugs Using Plasma HIV-RNA Measurements — Clinical Considerations for Accelerated and Traditional Approval.

The purpose of antiretroviral therapy is to suppress the viral load, called plasma HIV-ribonucleic acid (RNA) levels. The current way to go about this is typically with three antiretroviral drugs from two or more classes, and sometimes even more in certain patients. The new final guidance addresses the development of clinical trials to test novel antiretroviral drugs moving forward.

“For new HIV drug combinations of two or more or more early stage entities that are not expected to offer benefits over currently effective therapy, combination toxicology studies usually should precede phase II and phase III clinical trials evaluating the investigational combination as referenced in ICH M3(R2) [Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals],” the final guidance specifies.

The FDA stresses that the guidance does not address preventing HIV transmission with antiretroviral drugs. It also does not discuss how non-antiretroviral drugs should be developed.

The guidelines are broken down based on patient population:

• Group 1: Fully susceptible to all approved drugs, treatment-naïve, or previous treatment with a well-documented treatment history demonstrating no virologic failure.
• Group 2: Drug resistance to multiple drugs and multiple drug classes. Not able to construct a treatment regimen that can suppress HIV-RNA to levels below assay quantification limits.
• Group 3: Drug resistance present and able to construct a treatment regimen that can suppress HIV-RNA to levels below assay quantification limits.

The FDA recommends the following primary endpoints for phase 2 and phase 3 trials:

• For Group 1 trials: the proportion of patients with HIV-RNA levels less than the lower limit of quantification at 48 weeks using a sensitive, FDA-licensed test. If more sensitive tests are approved, sponsors are encouraged to base the primary endpoint on an approved test with the lowest lower limit of quantification. The method for calculating these proportions is described in Appendix A.
• For Group 2 trials: the proportion of patients with HIV-RNA decreases from baseline exceeding 0.5 log₁₀ at an early time point (up to two weeks). Other increments can also be used, such as 1 log₁₀ decline from baseline
• From Group 3 trials: the proportion of patients with HIV-RNA levels less than the lower limit of quantification at 48 weeks using a sensitive, FDA-licensed test. A 24-week time point can be used for superiority comparisons when a drug is expected to offer an advantage over currently available options.
• For Switch trials: the proportion of patients with HIV-RNA greater than or equal to the lower limit of quantification at 48 weeks using a sensitive, FDA-licensed test. This differs from the endpoints in Group 1 and 3 trials in that the endpoint focuses on and is powered for virological failure and not success. This is because in Switch trials patients are starting with HIV-RNA levels that are already suppressed below the assay limit of quantification. In other words, the endpoint of interest is the proportion of people with suppressed HIV-RNA at baseline who lose virologic control after switching to a new drug or regimen.

The secondary endpoints should focus on:

• Mean changes in viral load from baseline for treatment-experienced patients
• Changes in CD4⁺ cell counts from baseline

Time points for measuring viral RNA will vary depending on the patient population in the study, but early assessments (with one to four weeks) are particularly important in Group 2.

“Because treatment of HIV requires multiple drugs to achieve and maintain viral suppression below detection and to reduce the emergence of drug resistance to single drugs and drug classes, treatment INDs [investigational new drugs] that include two or more investigational drugs or that allow co-enrollment in several treatment IND programs simultaneously are desirable,” the guidance concludes.