The phase III trial currently before the committee has been a subject of controversy, as outlined in the background document prepared for this meeting by FDA. The Treatment Action Group (TAG) has serious reservations about RV144 and the decision by the FDA to allow the trial to proceed as currently designed.
In the absence of HVTN 501, a successful outcome to RV144 would require additional phase III studies to tease apart the roles of the two vaccines in the observed protection. In other words, the concept that the trial is attempting to "prove" is that ALVAC-induced cellular immunity plus AIDSVAX-induced humoral immunity will be more protective against HIV infection than either approach alone, yet we have no idea whether ALVAC can offer any degree of protection against HIV infection (we do know that AIDSVAX alone -- whether B/B or B/E -- does not).
Lest it be assumed that the effect of adding AIDSVAX to ALVAC could only be additive, at least one study in macaques found that adding a gp120 protein boost to a vaccine designed to elicit cellular immunity resulted in a poorer outcome compared to the same regimen without the protein boost (see SL Buge et al., AIDS Res. Hum. Retrovir. 10:891, 2003).
To commit significant human and financial resources to a vaccine trial that cannot provide a definite answer to the question it purports to ask seems deeply foolish, particularly when there is widespread agreement that current funding for HIV vaccine research is inadequate. Based on this concern, TAG initially argued that the AIDSVAX boost should simply be dropped from RV144, allowing the study to definitively evaluate the protective efficacy of ALVAC vCP1521 (see Science 305;5681:180, 2004). Once volunteers began to receive AIDSVAX immunizations, however, this argument essentially became moot.
TAG would argue that the benefits of participating in a phase III trial that can, at best, only lead to additional trials and cannot provide definitive answers as to the protective efficacy of the two vaccines involved are rather unclear. At the recent Bangkok meeting, it was stated that >70% of participants so far enrolled in RV144 cited "altruism" as their primary motivation, which leads to the question of whether the participants are aware that -- even if successful -- the trial will not be able to lead directly to the approval of an HIV vaccine for their population, or any other.
The cancellation of HVTN 501 and the failure of the two AIDSVAX efficacy trials should have prompted a more thorough review of RV144 than seems to have occurred, and this review should have included input from NIAID's advisory body, the AIDS Vaccine Research Working Group (AVRWG) and the FDA. Instead, input from the AVRWG was not solicited until after the study quietly began enrolling in October 2003. It is possible that this process was negatively affected by the politicking that surrounded the merging of the Military HIV Research Program back into the Division of AIDS at the National Institute for Allergy and Infectious Diseases (NIAID). TAG's understanding is that NIAID had to commit to supporting RV144 to completion as part of this merger, which presumably limits the ability of NIAID and its expert advisors to mandate substantive changes to the protocol.
Response: "Yes," to co-primary endpoints. "No," to any reduction in sample size (in case there is a decline in incidence).
Response: "No," but will consider enrolling an extra 200 people in order to conduct an immunogenicity study.
Response: Criteria for stopping trial due to operational futility will be promulgated. Stopping rules based on scientific futility will not be developed.
In the apparent absence of any possibility of dropping the AIDSVAX component from RV144, TAG endorsed the original AVRWG recommendation as a reasonable attempt to address the shortcomings of a trial that was already underway. The fact that the RV144 investigators have chosen to only selectively adopt the recommendations is therefore profoundly disappointing. TAG encourages the committee to discuss these issues further with the AVRWG and the RV144 investigators.
Back to the TAGline January 2005 contents page.