AIDS VACCINE EFFICACY TRIAL WITH MULTIPLE CANDIDATES RECOMMENDED BY NIH GP160 ADVISORY COMMITTEE; TRIAL DESIGN, VACCINE CANDIDATES NOT DETERMINED
The Defense Department should proceed with a large-scale AIDS therapeutic vaccine efficacy trial but should include several vaccine candidates in addition to MicroGeneSys' gp160 vaccine, NIH's gp160 review panel unanimously recommended Nov. 23 at its meeting in Bethesda, Md. DoD fiscal 1993 appropriations include $20 mil. earmarked for a gp160 vaccine efficacy trial. The congressional language in the appropriation states that NIH, FDA and DoD must decide within six months from Oct. 6 whether to go ahead with an efficacy trial with MicroGeneSys' gp160 or use the money in an alternative trial. The research will be coordinated by the Walter Reed Army Institute for Research in Washington, D.C. The panel determined that a trial should proceed based on "non-traditional" criteria rather than the traditional standard of demonstrated clinical efficacy. In reaching that conclusion, the panel was asked by NIAID's Fauci to determine whether "there is sufficient information based on either non-traditional scientific criteria and/or other considerations to justify proceeding with a large Phase III therapeutic trial." The "non-traditional" criteria include surrogate markers such as CD4 cell count and viral burden. The current scientific data show that the HIV therapeutic vaccines are safe; yield novel immune responses; have shown varied impact on CD4 counts; and have not been proven to have an effect on viral burden. The panel debated the importance of various surrogate markers and whether they can be effectively associated with progression of disease. Some panel discussion focused on whether additional surrogate marker data should be gathered during the course of a vaccine efficacy trial. At the VIII International Conference on AIDS in Amsterdam, Dennis Klinman, FDA Retroviral Research Lab, raised the issue of expanding the marker base ("The Pink Sheet" Aug. 3, T&G- 8). One ongoing Phase II trial with gp160, conducted by Robert Redfield, Walter Reed Army Institute for Research, may further elucidate the role of surrogate markers; however, the data may not be available until next summer. Redfield recently has come under scrutiny for his interpretation of gp160 Phase I data. Col. Harry Dangerfield, Army Medical Research and Development Command, is charged with assessing whether Redfield's interpretation of the trial data is accurate. While agreeing with the "concept" that an efficacy trial should be conducted with multiple HIV therapeutic vaccine candidates, the panel did not recommend a trial design or specific vaccine candidates. National Institute of Allergy & Infectious Diseases Director Anthony Fauci, MD, recommended that subcommittees be established to look into the "nitty-gritty" of trial design. The subcommittees would consist of members of the gp160 panel as well as representatives from the outside. In addition, the recently-constituted NIAID HIV vaccine working group will be consulted. Along with MicroGeneSys' gp160, the other leading candidates that may be considered for a large trial are Genentech's gp120; the Austrian firm Immuno AG's gp160; and Chiron/Biocine's gp120 product. Representatives from the three firms said they are fully prepared to provide their vaccines for such a trial. NIH said it is reasonable to believe that, if approved, accrual for a large trial would not begin until FY 1994. * The panel's recommendation will now be submitted to the NIH Advisory Committee to the Director, which is scheduled to meet on Dec. 2 (see related item, T&G-1). Following approval by the committee, NIH Director Bernadine Healy, MD, will submit a report to Congress outlining the agency's position. It is possible that FDA may also sign on to that report. One option may be a large, simple trial (LST), which Susan Ellenberg, chief of NIAID's biostatistics research branch, presented to the panel. Ellenburg, who floated her concept at the panel's Nov. 5 meeting ("The Pink Sheet" Nov. 9, p. 11), expanded on her initial presentation. In particular, she noted that "substudies" could be included in the trial to address concerns raised about surrogate markers. The substudies could evaluate adverse effects, immunologic markers and minor clinical events. As an LST alternative, Ellenberg presented a "typical path" trial design that would ensure that vaccine efficacy has been suggested by the clinical data prior to implementation of a large-scale trial. FDA Center for Biologics Evaluation and Research official Karen Goldenthal expressed the agency's support for a large, simple trial. Goldenthal stated: "Overall, it does appear that this type of product is well suited to evaluation in a large, simple trial because of the toxicity profile and the relatively infrequent administration." Some panel members were concerned that the $20 mil. figure would not be adequate to fund a trial that may take up to six years to complete. Fauci asked the DoD to "cost out" what a large trial might require based on Ellenberg's models. Healy told the panel "not to get too hung up on specifically $20 mil. We all have the same goal....When you talk about out-year money, there is no reason why that can't be a priority within our budget as well as the Army's budget."
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