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Review and Reform

OAR Advisory Panel Would Meld 12 Trials Networks into One and Requests Improved Institute Collaboration

15 Studies of Oral Interferon

June 1996

The six Area Review Panels (ARPs) of the NIH AIDS Research Program Evaluation Working Group of the OAR Advisory Council (known informally, after the group's chairman Dr. Arnold J. Levine, as the "Levine committee") included one focused on clinical trials of AIDS therapeutics. Of the six ARPs, this was perhaps the most urgent from the perspective of people living with HIV. TAG's antiviral committee chairman Spencer Cox, who served on the clinical trials ARP, provided the following report.

Of the National Institutes of Health (NIH)'s $1.4 billion AIDS research budget, about 20% ($250M) is categorized as research on clinical trials. Of this sum, the ARP found, only about one half is devoted to high-quality clinical research on AIDS treatments. About one quarter is devoted to poorly designed or poorly justified studies, and about one quarter is devoted to research which, however meritorious, has little to do with AIDS. Despite a few genuinely outrageous wastes of money (such as $11M wasted by National Institute of Mental Health on a study of peptide-T which was neither worth mounting nor, in the face of unacceptably heavy drop-out rates, worth completing; or, to give a contemporary example, NIAID's fifteenth study of oral alpha interferon mounted in the face of clear evidence from fourteen previous studies that the preparation is useless, at best), the clinical trials review panel members recognized meaningful progress attributable to the NIH clinical research effort.

The panel's task, like that of the other area review panels, was greatly hampered by the outmoded information systems and obtuse accounting methods at the NIH. Due to differences in accounting, a program in one institute that cost $3 million might be essentially equivalent in cost to a $14 million program at another institute. In addition, the ways in which the various institutes coded grant monies made it very difficult to distinguish AIDS clinical therapeutic research from other kinds of research. However, the panel also recognized that the federal therapeutic AIDS research effort has been hampered by the failure of at least seven NIH institutes to collaborate with each other, which has been made all too clear by the development of twelve duplicative research networks. For example, the National Eye Institute (NEI) carries out research focusing on the ocular complications of end-stage cytomegalovirus disease (CMV retinitis) while ignoring the obvious fact that CMV end-stage disease is a multi-organ infectious complication of AIDS which contributes significantly, extra-ocularly, to morbidity and mortality.

The ophthalmologically-inclined SOCA mavens, however, forgot to measure relevant transocular parameters such as CMV viremia or viruria. We can control CMV in the eye for years, thanks to NEI, but we have no clue about how to control CMV in the bodies (extra-ocular) of people living with HIV. The NEI's Studies of the Ocular Complications of AIDS (SOCA) network studied therapies for CMV retinitis without substantive collaboration with the ACTG. As a consequence, says clinical trials review panel member Lynda Dee of AIDS Action Baltimore, little thought has been given to the systemic nature of both CMV and HIV infection. "SOCA has done a great job if treating retinitis were the same thing as treating CMV disease," Dee observed. "As it is, you'll have 20/20 vision as you're dying."

One of the panel's more controversial recommendations involved pediatric AIDS research. Dee observed, "It's just not clear that, given the reductions in vertical transmission of HIV that have occurred since the completion of ACTG 076, that we will have the statistical power to do large-scale pediatric clinical research in the U.S." The panel recommended that NIH carefully monitor recruitment into pediatric therapeutic trials, and consider moving funds to overseas efforts if the U.S. does not offer an adequate patient base.

The panel also recommended melding the existing twelve clinical research networks into one giant clinical research structure. The new network, centered in the National Institute of Allergy and Infectious Diseases (NIAID), would fund a core of sites with the capacity to do intensive laboratory work, including immunology, virology, and pharmacology, as well as a "clinical core" capable of following patients for clinical status, such as rates of opportunistic diseases and death. In addition, the network would be capable of adding investigators, including private physicians, for large-scale phase III/IV studies on an as-needed basis.

Other institutes would provide the network with funding and support for research on opportunistic diseases. The network would be governed by the researchers working within it, with guidance from an oversight committee at the OAR. All databases would be designed for compatibility to allow for cross-study analysis. The panel further recommended that all major clinical trials should be peer reviewed to ensure the highest quality of clinical research. It remains to be seen whether NIH bureaucrats, such as the institute directors so accustomed to treating their own research networks as boutique outfits, will be capable of the cooperation and collaboration necessary to optimize the NIH AIDS drug testing system.

As an example of a successful collaboration between institutes, the panel singled out the cooperation of the NIAID and the National Institute for Child Health and Development (NICHD) on the pediatric ACTG. Dee suggested that this program could serve as a model for the new network. The panel neglected, however, to express its concern that the Pediatric ACTG research agenda focused excessively on trying to prevent perinatal HIV transmission with discredited "therapeutic vaccine" approaches, while ignoring the opportunistic infections which actually kill children living with HIV.

The panel also recommended that the NIH organize appropriate peer review mechanisms to review outside proposals for small-scale investigator-initiated clinical research proposals. In reviewing intramural efforts at the various institutes (mainly NIAID and the National Cancer Institute (NCI)), the panel recommended strict scrutiny by the OAR to avoid redundancy. In particular, institutes were advised to focus their intramural efforts on programs that utilized their unique expertise as well as the particular opportunities offered by the NIH clinical center. This is a euphemism for saying the NIH clinical center, which offers nothing unique save for exemption from peer review, should survive.

With respect to alternative therapies, the panel agreed with many AIDS activists that evaluation of the safety and efficacy of such treatments was a reasonable goal, but expressed concern that such research currently seems to "lack the explicit commitment to evaluate the scientific bases and medical outcomes of alternative therapies with established, rigorous methodology." The report recommends greater use of well-designed, controlled studies, including objective measurement of outcome, and careful assessment of toxicity. It is a pity NIAID is wasting precious AIDS research funds on a poorly-justified, redundant study of oral alpha interferon.

Overall, the panel felt that new developments in therapies for AIDS and its associated opportunistic diseases offered remarkable opportunities and important challenges. Acknowledging that current structures had contributed greatly to AIDS therapy, members nonetheless believed that these structures were not sufficient for the kinds of studies that would be needed. Greater flexibility, less redundancy, and improved cooperation are desperately needed as researchers face coming research needs. For example, third-party payers are demanding clearer data regarding protease inhibitors, which, while appearing more antivirally active than approved nucleoside analogues, are also three times as expensive, with unique toxicities. NIH currently lacks the infrastructure to carry out post-marketing efficacy studies of these agents. Regardless of their potential benefit, if Americans with HIV disease cannot access these drugs, or use them with maximal benefit, the fruits of biomedical research will rot on the vine.