Treatment Issues: Newsletter of Experimental AIDS Therapies - Volume 15, Number 5, May 2001

The U.S. government's premier clinical trials group for studying HIV therapies is adrift. The HIV Research Agenda Committee (HIV RAC) of the Adult AIDS Clinical Trials Group (AACTG) sees its mission as performing small, scientifically challenging studies that quickly respond to emerging questions about HIV pathogenesis and treatment. In reality, its studies seem to respond to an entrenched leadership's myopia, powerful drug company interests and an institutional need to justify expensive technical resources.

AACTG protocols are slow to develop and often lag behind critical questions when finally launched. Once open, many AACTG trials fail to enroll patients due to therapeutic irrelevance, complex treatment schemes or unrealistic entry criteria. Many of the trials currently open to enrollment derive from concepts that entered development in the late nineties — and several trials opening during that period have languished from lack of interest.

Of the six AACTG HIV-disease trials currently offering drugs to participants, five include the GlaxoSmithKline HIV products, Agenerase or Ziagen. These approved medications have failed to catch on with clinicians and patients due to an unpleasant pill burden or fears about toxicity, and they rank near the bottom of U.S. HIV pharmaceutical sales. Yet multiple studies of these two drugs, arguably more appropriately sponsored by the manufacturer, seem to be a priority for the AACTG.

This should raise a question about the degree that Glaxo's interests are represented at the AACTG. Dr. Robert (Chip) Schooley, Chair of the AACTG's Executive Committee, participated as a non-AACTG investigator on two early Glaxo-sponsored trials of Agenerase and Ziagen — the two drugs dominating current AACTG treatment trials. One could argue that Dr. Schooley's experience with these drugs in the Glaxo trials convinced him of their potential importance. Yet, despite increasing discussion in medical journals about the problem of improper pharmaceutical industry influence over academic research, AACTG leadership has clearly failed to appreciate the appearance of a conflict of interest in this case.

The Chair of the HIV RAC at the time these AACTG trials were developed was Dr. Daniel Kuritzkes, an associate faculty member at the University of Colorado Health Sciences Center in the Division of Infectious Diseases. Dr. Schooley is the head of this division. As Chair of the AACTG's Executive Committee, Dr. Schooley, along with Dr. Constance Benson, a full professor in Dr. Schooley's division, have exerted a powerful influence over research priorities at the AACTG. This concentration of power in one department at one university and the possibility that a subordinate role on the faculty affected Dr. Kuritzkes's independent direction of the HIV treatment research agenda is troubling.

The problems with the AACTG may ultimately have more to do with its structure than its leadership. Once every five years, the AACTG applies for several hundred million dollars in government funding. The Group's application undergoes a nominal review, but with no other network in competition, it is invariably refunded. Then, for the ensuing five years, the AACTG is left to manage itself, with little specific peer-review of its scientific hypotheses, proposals or progress. One could argue that this system creates an atmosphere ripe for intellectual complacency, if not worse.

One idea for reforming the AACTG proposes that NIAID no longer try to maintain a standing network, but instead ask individual institutions to apply for grants in collaboration with other institutions to answer specific clinical research questions. These resulting 'virtual research networks' would be more adaptable, could be constituted with specific expertise and resources to answer particular questions, and be disassembled after a study was complete — a new network arising to answer the next clinical dilemma.

Innovative research proposals remain scarce among AACTG concepts in development. A publicly funded trials network unable to step up to fundamental questions such as "How do immune responses differ in women,"or "When should one start taking HIV drugs?" is avoiding its duty. But when a key part of that program commits half its capacity to seek incremental knowledge about a single manufacturer's products, it is derelict and needs to be overhauled.

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