Phase III clinical studies for multi-drug resistant HIV need to evolve from traditional superiority or non-inferiority designs to a new approach in which clinical improvements are demonstrated through short, step-wise efficacy and safety trials, argues a US-based stakeholder group.

The proposals come from the Washington-based Forum for Collaborative HIV Research, which represents government, industry, researchers, patient advocates, healthcare providers and private foundations.

It was set up 15 years ago in response to a White House initiative calling for ongoing collaboration among stakeholders to address emerging issues in HIV/AIDS and to map out an appropriate research strategy.

The proposed new pathway for Phase III trials features in the 1 February 2012 electronic issue of the journal AIDS.

According to the Forum, what is now a “robust” drug development pipeline for HIV risks being undermined by the challenge of showing efficacy and safety in clinical trials of promising new antiretrovirals in either ‘treatment-experienced’ or ‘treatment-naïve’ patients.

In these circumstances, the Forum says, superiority or non-inferiority trials are “no longer useful” as a means of demonstrating clinical improvements.

Sharp decline

The new pathway outlined in the AIDS paper focuses on HIV trials in multi-drug resistant patients, where rates of accrual into HIV clinical trials have declined “precipitously”, the Forum notes. This is due largely to increasing use of boosted protease inhibitors and the enhanced potency and efficacy of antiretroviral regimens overall, it explains.

From 2006 to the present, the rate of recruitment for trials of treatment-experienced patients with multiple drug resistance has fallen from 1.15 to 0.02 participants per month, “even though sponsors are using an ever increasing number of study sites and countries”, the Forum says.

For these patients, short, cumulative superiority trials would allow sponsors to demonstrate efficacy without the risk of patients developing resistance to the new drug or additional resistance to old drugs, it argues.

Multi-phase design

The pathway described in the AIDS paper calls for a multi-phase study design including:

•    A short trial (10-14 days’ duration) comparing the investigational compound and placebo, with the patient’s current failing regimen as background therapy, to evaluate short-term efficacy in viral-load reduction.             

•    A follow-on study in which all the participants receive the investigational drug (at a single or different doses) and are assessed at 24 weeks to evaluate dose response, safety, durability of initial response and development of resistance.         

•    A possible second comparative safety trial in patients with a minimum of two active drugs available, where participants are randomised to the investigational agent plus a new optimised background regimen of antiretroviral drugs, versus a new optimised background regimen plus placebo.

These options are not so applicable to studies in treatment-naïve patients, “where results of both superiority and non-inferiority trials are difficult to interpret”, the Forum points out.

With superiority trials, the challenge in treatment-naïve patients is that current first-line antiretroviral regimens produce viral suppression rates exceeding 90% in this population, it explains. With non-inferiority trials, the problem is more about elucidating true differences between drug regimens.

“For these reasons, there is no consensus on the utility of studying investigational agents in this patient population, although scientists, regulators and drug sponsors recognise these HIV drugs may offer treatment-naïve patients better tolerability or reduced long-term safety risks than currently available options,” the Forum comments.

Wide range of therapies

As the paper notes, there are now 26 unique antiretroviral drugs (plus alternative formulations and fixed-dose combinations) in six different therapeutic classes available to treat HIV. Together they have achieved viral suppression rates of between 70% and 90%.

However, the authors also highlight growing problems with drug-resistant strains of HIV and the ongoing need for new treatment options.

“Despite the many valuable antiretroviral drugs now available to treat HIV, new antiretrovirals can bring important benefits, such as fewer side-effects, less frequent dosing and a lower risk of drug resistance,” comments Veronica Miller, director of the Forum and one of the authors of the paper.

“That is why overcoming the barriers to innovation in HIV drug development is so critical,” Miller adds. “Our paper offers a new pathway for regulatory approval of promising new HIV drugs and reflects the best thinking of the top experts in the field.”