Novel clinical trial designs for the development of new antiretroviral agents

Abstract

The resounding success of combination antiretroviral efficacy for both treatment-naïve and -experienced patients – with 70% – 90% viral suppression rates in recent studies–has made registration trials for new agents challenging. With the inevitable specter of drug resistance, new agents must have a pathway to approval. The Forum for Collaborative HIV Research obtained input from concerned stakeholders including industry, clinical sciences, community advocacy and regulatory sciences (Food and Drug Administration and European Medicines Agency) to discuss how safety and efficacy of new agents could be demonstrated. Recognizing the shortfalls of superiority or non-inferiority trials in this environment, a new trial design for treatment-experienced patients, minimizing the risk for drug resistance but allowing full assessment of safety was proposed. The antiviral efficacy of an active investigational drug would be assessed by comparison to placebo as an add-on to a failing regimen in a short, 10–14 day study followed by institution of an optimized background regimen in both arms with investigational drug given to all patients. The follow-on stage would assess dose response, safety, durability of initial response and development of resistance. Additionally, a second safety trial could be conducted comparing patients randomized to the investigational agent plus a new OBR to those on a new OBR plus placebo. Finally, approval decisions could consider other long-term safety endpoints. Exposing treatment-naïve patients to investigational agents remains a controversial issue; stakeholders have different interpretations of risk-benefit for trials in this population which necessitate careful consideration before initiating trials in them.

Some current issues in the design of HIV noninferiority trials

“…The protocolspecified noninferiority margin is intended to reflect the maximum clinically acceptable difference between the therapeutic alternatives, as well as to prevent successive erosion of efficacy as new agents become the old standards in future trials [30][31][32]. In reality, however, the margin is mostly driven by logistical considerations around sample size and power calculations [2,19,31,[33][34][35]. In addition wide margin increases the probability of lying in a difficult situation in which the entire 95% CI lied within the noninferiority margin and the 0 bound [30,36].…”

“…The efficacy of HAART has led to a move towards the use of noninferiority designs for HIV drug development [1,2]. Indeed, with viral suppression rates of 80-90% in recent studies, it would be difficult to design a superiority trial showing any meaningful improvement.…”

“…It has been argued that such a reduction would lead to a large increase in sample size [2]. Indeed, the width of the noninferiority margin drives the overall sample size (Fig.…”

Vicriviroc plus optimized background therapy for treatment-experienced subjects with CCR5 HIV-1 infection: Final results of two randomized phase III trials

“…This approach may provide an alternative route for regulatory assessment of new antiretroviral drugs. Recently, Mani et al, 15 suggested clinical trial design options for the development of new antiretroviral agents for treatment-experience patients. The authors proposed that efficacy of a new antiretroviral drug in treatment-experience patients could be examined by comparison to placebo as an add-on to a failing regimen for a 10e14 day period followed by initiation of a new OBT in both arms of the study with the investigational antiretroviral drug given to all the subjects.…”

Fostemsavir in Heavily Treatment-Experienced Individuals Living with HIV-1: Insights from the Phase 3 BRIGHTE Study

“…Long-term placebo-controlled comparisons are also not appropriate because continued use of an unmodified failed ARV regimen would increase the risk of emergent resistance to the investigational drug and progression of disease. The BRIGHTE study was designed to address these challenges in accordance with guidance on the development of ARVs for the HTE population [10,11]. Building on data from a phase 2b study (ClinicalTrials.gov, NCT01384734) that had demonstrated favorable efficacy, safety, and tolerability of fostemsavir in treatment-experienced PLWH [12,13], BRIGHTE aimed to further assess the efficacy and safety of fostemsavir and also to fulfill the crucial unmet medical needs of HTE PLWH.…”