On November 2, 2015, FDA released a final guidance entitled “Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment,” concerning the development of drugs for the treatment of Human Immunodeficiency Virus (HIV). The guidance is organized in a way that ‘parallels’ the development plan for a drug or biologic and it is intended to address “the overall development program and clinical trial designs for antiretroviral drugs to support an indication for the treatment of HIV-1 infection.”
The document starts out by listing the topics that will not be addressed or discussed in the guidance. These include:
- The use of antiretroviral drugs for preventing transmission of HIV-1 infection.
- The development of therapeutics without antiviral mechanisms, intended to mitigate or reverse clinical or pathophysiological outcomes of immunologic suppression caused by HIV-1 infection.
- General issues of statistical analysis or clinical trial design.
The document states that “details regarding nonclinical safety and toxicology studies that should be conducted in standard animal models as described in the guidance for industry Nonclinical Safety Evaluation of Drug or Biologic Combinations” are not included in this guidance.
Prior to 1997, “traditional approvals were based on clinical endpoint trials assessing the effects of a drug on mortality and/or progression of HIV disease.” When FDA realized that requiring clinical endpoint trials was no long feasible for all traditional approvals, the Agency assembled the Antiviral Drug Advisory Committee. The advisory committee meeting was held “to consider the use of changes in HIV-RNA levels as endpoints in clinical trials supporting traditional approval of antiretrovirals.”
Between 1996 and 1997, a group of pharmaceutical, academic, and government scientists conducted an investigation where they identified “a relationship between initial decreases in plasma HIV-RNA levels and reduction in the risk of clinical progression and death, which was observed across a range of patient characteristics.”
Based on this finding, FDA’s Antiviral Drug Advisory Committee concluded that levels of HIV-RNA reduced over a shorter period of time could be used to support accelerated approvals. The advisory committee also stated that are more long term reductions could be used to support traditional approvals.
The final guidance provides recommendations for the development of antiretroviral drugs that are intended for the treatment of HIV and are regulated within the Agency’s Center for Drug Evaluation and Research (CDER).
In the document, FDA defines three patient groups:
- Fully susceptible to all approved drugs, treatment-naïve or previous treatment with a well-documented treatment history demonstrating no virologic failure.
- Drug resistance to multiple drugs and multiple drug classes and unable to construct a regimen that suppresses HIV-RNA to below assay quantification limits.
- Drug resistance present and able to construct a regimen that suppresses HIV-RNA below assay quantification limits.
The Agency recommends the primary efficacy endpoints for phase 2 and phase 3 trials for group 1, 2, and 3 trials, as well switch trials (or trials where patients who are already suppressed on one treatment are changed to a new treatment regimen, as defined by RAPS).
Additionally, the guidance states that secondary endpoints should include the following:
- Mean changes in viral load from baseline for treatment-experienced patients.
- Changes in CD4+ cell counts from baseline.
Included within the document are considerations regarding the development program of these products and expectations for the design of switch trials. The guidance states that it will no longer be necessary for companies to seek accelerated approval followed by traditional approval, because “HIV-RNA is a validated surrogate for predicting efficacy of antiretrovirals.”
The Weinberg Group has a proven track record of helping our clients get through FDA successfully. For assistance with the development and approval of an antiretroviral product or any other drug products, email us here.