The resounding success of combination antiretroviral efficacy for both treatment-naïve and treatment-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 noninferiority 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 (OBR) 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 with a new OBR to those on a new OBR and 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 that necessitate careful consideration before initiating trials in them.
aForum for Collaborative HIV Research, University of California-Berkeley, Washington, District of Columbia
bFood and Drug Administration, Silver Spring, Maryland
cWeill Medical College of Cornell University, New York, New York, USA
dSwedish Medical Products Agency, Uppsala, Sweden
eCurrent affiliation: RxBio, Inc., Washington, District of Colombia, USA.
*Disclaimer: The contents of this paper represent the considerations and reflections of the authors, and not necessarily the views of the Food and Drug Administration or the Swedish Medical Products Agency.
Correspondence to Nina Mani, 1608 Rhode Island Avenue NW, Washington, DC 20036, USA. Tel: +1 202 974 6220; fax: +1 202 872 4316; e-mail: email@example.com
Received 5 December, 2011
Revised 5 January, 2012
Accepted 18 January, 2012