HIV Experts Propose New Pathway for Conducting Phase 3 Drug Trials

New Approach Intended to Remove Barriers to Innovation in Drug Development

WASHINGTON, Feb. 7, 2012 /PRNewswire-USNewswire/ -- As the war on HIV/AIDS begins its fourth decade, medical researchers, pharmaceutical manufacturers, patient advocates and government regulators face a new and unexpected scientific challenge: how to demonstrate the safety and efficacy of promising new antiretroviral drugs when the two traditional study designs – the superiority trial and the non-inferiority trial – are no longer useful in showing improvements in both "treatment experienced" patients and those who have never received drug therapy (treatment-naive patients).

Because this challenge could have a dampening effect on what is now a robust drug development pipeline for HIV, the Forum for Collaborative HIV Research has just released a new scientific paper that lays out a substantially different approach for conducting Phase 3 HIV clinical trials. 

Published in the journal AIDS, the paper summarizes the insights of specialists from the Food and Drug Administration, European Medicines Agency, academia, the patient advocacy community and industry that overcoming the current difficulties in conducting new HIV drug trials requires moving from the large-scale study model to a new approach where clinical improvements are demonstrated through a sequence of short, step-wise efficacy and safety studies.

"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. That is why overcoming the barriers to innovation in HIV drug development is so critical," said Veronica Miller, Ph.D., Director of the Forum and one of the authors of the paper. "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."

The new pathway described in the paper calls for a multi-phased study design, which includes:

• A short study (10-14 days) comparing the investigational compound versus placebo, with the patient's current failing regimen as background, to evaluate short-term efficacy in viral load reduction
• A follow-on study where all 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
• The possibility of a second comparative safety trial in patients with a minimum of two active drugs available where participants are randomized to the investigational agent plus a new optimized background regimen of antiretroviral drugs versus patients on a new optimized background regimen plus placebo

Intended to preserve innovation in HIV drug development, the new proposed pathway focuses specifically on trials in multi-drug resistant patients, where rates of accrual into HIV clinical trials have declined precipitously, due largely to the increasing use of boosted protease inhibitors and the overall enhanced potency and efficacy of antiretroviral regimens. From 2006 to the present, the rate of patient recruitment for trials of treatment-experienced participants with multiple drug resistance has fallen from 1.15 per month to 0.02 per month even though sponsors are using an ever increasing number of study sites and countries. For these patients, the new approach of a short, step-wise superiority trial allows sponsors to demonstrate efficacy before the risk of developing resistance to the new drug or additional resistance to the old drugs can take place.

These new options are not as promising for conducting studies in treatment-naive patients, where results of both superiority and non-inferiority trials are difficult to interpret. With superiority trials, the challenge is that current first-line antiretroviral regimens produce viral suppression rates exceeding 90 percent in this patient population, making these studies impractical. With non-inferiority trials, the problem is that true differences between drug regimens can be difficult to interpret. For these reasons, there is no consensus on the utility of studying investigational agents in this patient population, although scientists, regulators and drug sponsors recognize these HIV drugs may offer treatment-naive patients better tolerability or reduced long-term safety risks than currently available options.

Reflecting the realities of today's environment, the new paper notes the availability of a wide range of antiretroviral agents -- 26 unique antiretroviral drugs (plus alternative formulations and fixed-dose combinations) from six different therapeutic classes – which collectively have produced viral suppression rates of between 70 percent and 90 percent. But the paper also reflects the growing problem of drug resistant strains of HIV and the ongoing need for new treatment options. Accordingly, the proposed changes in HIV trial design are intended as a pathway for regulatory approval of promising new drugs that will address multi-drug resistant virus while also offering patients advantages in safety and tolerability for patients.

The new scientific paper, "Novel Clinical Trial Designs for the Development of New Antiretroviral Agents," appears in the February 1, 2012 electronic issue of the journal AIDS (doi: 10.1097/QAD.0b013e3283519371; accessed February 6, 2012).

About the Forum for Collaborative HIV Research
Now part of the University of California (UC), Berkeley School of Public Health and based in Washington, DC, the Forum was founded in 1997 as the outgrowth of a White House initiative which called for an ongoing collaboration among stakeholders to address emerging issues in HIV/AIDS and set the research strategy. Representing government, industry, patient advocates, healthcare providers, foundations and academia, the Forum is a public/private partnership that is guided by an Executive Committee that sets the research agenda. The Forum organizes roundtables and issues reports on a range of global HIV/AIDS issues, including treatment-related toxicities, immune-based therapies, health services research, co-infections, prevention, and the transference of research results into care. Forum recommendations have changed how clinical trials are conducted, accelerated the delivery of new classes of drugs, heightened awareness of TB/HIV co-infection, and helped to spur national momentum toward universal testing for HIV. http://www.hivforum.org 

SOURCE Forum for Collaborative HIV Research