Materials and Links

Re-thinking the Design of Clinical Trials for the Development of New ARVS for Treatment Experienced and Treatment Naïve Patient Populations  

Background:

Drug development for the treatment of HIV infection has proceeded at an unparalleled pace. The approach that was adopted for clinical development -- including accelerated preliminary approval-- has facilitated the expansion of two drug classes available prior to 1995, to 6 drug classes by the end of 2007. While the palette of drugs from which to construct a regimen is significantly more expansive than it was in the past, the HIV community remains in need of additional new drugs to treat drug resistant virus as well to ensure safety and tolerability for all populations.

It is now time to reconsider our approach to drug development in order to ensure the highest level of safety for patients participating in clinical trials while maintaining an adequate pipeline of new drugs. The goals of the Forum for Collaborative HIV Research Roundtable are to review, discuss and develop consensus in the field of antiviral drug development. These discussions will help to identify the best mechanisms to study drugs for treatment experienced and treatment naïve patients from the US and European perspective.

Objectives:

I. Treatment-Experienced Study Topics

For purposes of discussion, we should define the relevant population for whom designing comparative trials is challenging. In the past (2001) we defined treatment-experience as patients who had a loss or lack of virologic response to at least two HAART regimens that, in total, have included at least one member of each of the approved drug classes (NRTI, NNRTI and PI). In other words, we propose to define the populations based on what they have available to them rather than what they have failed on.

1. Definition of patient population :
   1. Patients who have treatment options (e.g. 2 or more active drugs)
   2. Patients who do not have treatment options (e.g. 1 or no active drugs)
      
2. Definition/algorithm for establishing genotypic or phenotypic sensitivity scores/overall susceptibility scores to determine background regimen.
   1. The Forum’s Standardization and Clinical Relevance of HIV Drug Resistance Working Group will develop a background paper outlining the various approaches that have been used for GSS and PSS; outline the drawbacks and benefits for each approach
   2. FDA, EMEA and academic advisors will make a proposal re more standardized use of GSS and PSS and ask for feedback during the meeting
   3. Develop principles of how to handle discrepancies between genotype and phenotype information
   4. Issue of viral tropism should be mentioned as another factor that goes into the decision making, but not include in the GSS and PSS
      
3. Study Design/Control Arm
   1. Question: Please comment on the strengths and weaknesses of the trial design options presented.
      1. In class non-inferiority comparison
      2. Across class non-inferiority comparison
      3. Add on to OBT - superiority
      4. fixed background regimen vs OBT, vs mandating at least two fully susceptible drugs in the background regimen (including all available EAP agents)
      5. Other designs
         
4. Study Duration – if studies mandate at least two fully susceptible drugs in the background regimen what is the optimal study duration to establish safety and efficacy (24 vs 48 weeks).
   
5. Endpoint – We propose a < 50 copies/mL endpoint as a preliminary definition for the meeting discussions
   
6. Statistical issues – non-inferiority margin – the need to have a discussion on this topic should be mentioned, but in depth discussion on this topic to be tabled for another venue
   
7. Proposal for new indication in treatment-experienced patients –indicated “for treatment of HIV-1 infection in combination with other antiretroviral agents in treatment-experienced patients with evidence of HIV -1 replication despite ongoing antiretroviral therapy” vs resistance test outcome based indication.

Treatment-Naïve Study Topics

This will be relevant for drugs for which the intent is to obtain an indication for both, treatment naïve and treatment-experienced indication.

1. When in the drug development timeline to start naïve studies with new drug classes? What amount and type of data is needed prior to initiate studies in naïve patients? Acceptability of initial dose finding in naïve patients.
2. Study duration for naïve indication – 48 weeks or longer

Status:

The meeting was held on January 10-11, 2008 in Washington DC. A summary of the meeting outcome has been published in AIDS 2008, 22:2419–2427.