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Problems In Implementation LOUD AND CLEAR: Attorney Lynda Dee stresses the need for communication among the institutes. When a federally appointed panel announced in March the results of its 15-month-long review of the United States government's AIDS research program, AIDS activists as well as scientists cheered. The National Institutes of Health's AIDS Research Program Evaluation Working Group's recommendations largely called for scrapping what the group saw as outdated and ineffective policies, and opened the door for more coordinated, focused research efforts. For scientists in particular, the proposed changes were welcome: The report explicitly cited the need for doubling funding for investigator-driven research. Yet many who praised the report still cast a wary eye on the working group's suggestions. Some continue to take a wait-and-see attitude. Overhauling the nation's AIDS research program is no simple task, and implementing some admittedly grandiose plans will not be easy. "How specific recommendations will play out over time is hard to say in advance, as NIH figures out what [the recommendations] really mean," says Alan Leshner, director of the National Institute on Drug Abuse. He and 23 other institute directors are waiting for reports from six individual panels, scheduled for release later this month, that will spell out specific recommended changes. In all, 118 leading scientists and other representatives of academia, industry, community organizations, and AIDS advocacy groups evaluated AIDS research programs across 24 NIH institutes, determining what to keep, change, or throw out. The report, an executive summary of those evaluations issued by the working group, was critical of several areas of NIH's AIDS research program. In "numerous instances, [NIH] unfortunately appears to have failed in identification of the most promising research projects," the report said. It also criticized "inappropriate classification" that has "led to allocation of AIDS research funds to activities with little or no direct relevance to AIDS." Furthermore, it said NIH spends too little on ideas initiated by scientists outside the government. The working group noted that research efforts often are poorly coordinated. For example, the report was critical of the National Cancer Institute's Developmental Therapeutics Program (DTP)-NCI's drug-development program-noting it had "limited" productivity in producing novel agents and in many cases replicated pharmaceutical industry efforts. It said that "attempts at collaborative research between programs have been hampered by the lack of standardized databases." The report suggested combining all adult clinical-trials programs into a single network. It also called for restructuring and cutting AIDS DTP funding. The report made 14 major recommendations (see list on page 4). Among them, it suggested doubling investigator-initiated research funding, establishing a clinical-trials system to be coordinated through the National Institute of Allergy and Infectious Diseases (NIAID), and appointing a government-led task force to head up an effort to develop an effective AIDS vaccine. Several institute directors have begun meeting with NIH director Harold Varmus and with William Paul, director of NIH's Office of AIDS Research (OAR), to discuss potential implementation of the suggestions in the working group's report. Molecular biologist Arnold J. Levine, discoverer of the p53 tumor suppressor gene, chaired the working group. Levine, chairman and professor of Princeton University's department of molecular biology, calls the report "an excellent mid-course correction" to NIH's 15-year AIDS research effort. So far, he notes, "the feedback from the science community and from industry has been good." CHANGE IS GOOD: Richard Whitely says report will have "major impact". Others see vast opportunities resulting from the report. "I think that the recommendations potentially will have a major impact on AIDS research in the United States," says working group member Richard Whitley, a professor of pediatrics, microbiology, and medicine at the University of Alabama in Birmingham and head of the clinical trials panel, one of six groups carrying out a review. Susan DeLaurentis, cofounder and CEO of the Pediatric AIDS Foundation in Santa Monica, Calif., and a member of the OAR Advisory Council, comments: "All of the recommendations are moving in the right direction. This is a real opportunity for the entire AIDS research effort to be redefined, reinvigorated, and streamlined, and we think every part of it bodes well for the AIDS effort." TRIAL RUN: Activitst Kiyoshi Kuromiya sees new opportunities. Kiyoshi Kuromiya, project director of the Critical Path AIDS Project Inc. in Philadelphia, says the working group report has "the potential for being a big new step in HIV research." He's convinced that the scope of the report's recommendations, in addition to the influence of the panel members themselves, will ensure that "this isn't just another program review that will sit on a shelf." While most scientists applaud the sweeping recommendations, they also contend that their implementation remains the greatest challenge ahead. One reason is the ongoing battle between OAR and Congress for the authority to disburse federal AIDS funding to the various institutes. Yielding to congressional pressure, NIH agreed in February to give its 1996 AIDS research budget of $1.4 billion directly to the 24 individual institutes rather than funnel the money through OAR, which it had done since 1993. OAR director Paul, however, doesn't seem worried about his office's authority. He contends that even without control of the budget, OAR continues to influence the allocation process: It develops a comprehensive plan for AIDS research and determines how much each institute will need for its OAR-sanctioned projects. At an NIH news conference announcing the report's results in March, Paul, an immunologist, stated: "The NIH as a whole is deeply committed to moving ahead quickly with these recommendations." Some institute directors are rumored to resent the role of OAR in developing research plans and AIDS funding amounts. One director, speaking on condition of anonymity, calls OAR "demanding and difficult to work with," noting that it attempts to "micromanage" AIDS-related institute projects. Etiology and pathogenesis panel member Gregg Gonsalves, who chairs the legislative affairs committee of Treatment Action Group (TAG), a New York-based AIDS activist organization, previously told The Scientist (Notebook, Aug. 21, 1995, page 30) that he suspected institute directors were concerned that OAR might find better uses for institute money "that's nominally being called AIDS [funding]." He argues that those directors who fear losing funding are "thumbing their noses at the extramural scientists' community and those who authored the Levine report" by lobbying Congress to effectively reduce OAR's control of the AIDS budget. RECOMMENDATIONS OF THE AIDS WORKING GROUP Date: May 13, 1996 The NIH AIDS Research Program Evaluation Working Group report lists 14 major recommendations to the Office of AIDS Research Advisory Council: Increase support for and improve peer review of ivestigator-initiated research. Establish a restructured, trans-NIH vaccine research effort. Augment research efforts to better understand the immune system. Develop a comprehensive NIH HIV-prevention science agenda. Integrate all adult clinical-trial programs into a single network. 6. Refocus and restructure the drug-discovery research effort. Augment basic science research on AIDS-associated opportunistic infections and facilitate transfer of new findings to early clinical evaluation. Strengthen the scientific base for assessing complemantary and alternative medicine therapies for HIV disease. Reorganize procedures to ensure that Regional Primate Centers are available and responsive to unaffiliated scientists. Strengthen AIDS research centers to promote multi- disciplinary research on the disease. Ensure that central repositories of biomedical specimens and databases are of the highest quality and accessible to qualified investigators. Upgrade the NIH AIDS Research Information System database and increase the information base. Develop and implement a clear definition of AIDS and AIDS-related research through an evolving process. Preserve a strong Office of AIDS Research to provide leadership and coordination to the entire NIH AIDS research program. "House Republicans have been doing the bidding of the institute directors and trying to strip OAR of its budget authority," Gonsalves asserts. "They've left the OAR with an uphill battle" to implement the report's recommended changes. National Heart, Lung and Blood Institute (NHLBI) director Claude Lenfant contends that he wasn't particularly "troubled" by the OAR review, although his institute was criticized for carrying out research now deemed unrelated to AIDS. But he argues that tightening the definition of AIDS-related research may not be a good idea. Specific diseases frequently benefit from research in seemingly unrelated areas, he notes. Categorizing research as either related or not related to AIDS may be difficult as scientists continue to learn more about the illness, he maintains. Lenfant also is concerned about increasing nongovernment investigator research at the expense of institute programs, which may have clearer overall objectives. Industry scientists, however, disagree. "As NIH-investigator-initiated research improves, in theory industry's job will become easier because of a larger knowledge base," says Emilio Emini, executive director of the department of antiviral research at Merck Research Laboratories, headquartered in Rahway, N.J. Emini, who chaired the drug discovery panel, observes: "In the case of drug discovery, NIH's role has largely been to fund the basic research that leads to the discovery of fundamental knowledge. It's done that very well, but it can do better." While the report is highly critical of the government's AIDS research program, the document itself has received criticism for its lack of specifics. ACT-UP New York activist George Carter is upset with the report's lack of attention to funding specific research on alternative AIDS therapies. He argues that the "same old ineffective drugs" continue to be studied. Even working group members concede a lack of specific solutions. Whitley's panel noted that one of the factors limiting efficiency of clinical research was an inability to easily share data. "We called for significant spending to get databases to talk to one another so you can get cross-talk between clinical trials," he says. "Unless this happens, we'll lose information and precious patient resources." Whitley was "surprised by the overall lack of coordination at NIH. The strongest recommendation from every panel was to improve communication among individual institutes." Yet he acknowledges that a single clinical-trial network could be cumbersome. What's more, the expense involved in establishing a single data network, he notes, will be significant, though he thinks it will pay off in the long run. Nonetheless, Whitley believes that the individual institutes will support the working group recommendations. "Bill Paul will need to get the support of the institute directors," he says. "I have all the confidence in the world that the institutes want to move these recommendations through implementation quickly. I don't see many problems with this." While he applauds the overall working group effort, Philip K. Russell, a professor of international health at Johns Hopkins University and president of the New Canaan, Conn.-based Sabin Foundation, believes the working group report "lacks some clarity and specificity in moving ahead in the future." Russell is disappointed in the recommendations for improving the federal vaccine development effort. Though the report properly outlines deficiencies in current vaccine research, Russell says, he is not sure the solutions are the most effective ones. "I see more bureaucracy than effectiveness in their proposed solutions," he states. The panel suggested that NIH's vaccine development program be overhauled and that a nongovernment scientist be appointed to oversee a newly created program involving the entire NIH. It urged President Clinton to appoint a White House-level task force to coordinate all government-sponsored vaccine research. Russell asserts that a government-industry consortium may be a solution to the lack of industry interest in vaccine development. Activist and working group member Kuromiya sees new opportunities in the working group report, particularly in its recommendations to study complementary and alternative medicine. "Many are in wide use in the community, and we need to know whether they are effective or not," he explains. Kuromiya contends that the new recommendations provide an "opportunity to have more community-based trials." The review was anything but a simple undertaking. Most reviewers report that an unstructured NIH record-keeping system made their jobs much tougher. "It's hard to track the funding dollars because of how NIH accounting and reporting are set up," notes Spencer Cox, TAG's antiviral committee chairman and a member of the clinical trials panel. "We recommended a uniform accounting system." Indeed, many panel members contend that evaluating funding efficiency in the various categories is particularly complicated because project data collection is not uniform across institutes (B. Goodman, The Scientist, July 10, 1996, page 1). UP FOR GRABS: Don Des Jarlais wonders who will control the budget. Working group member Don Des Jarlais, director of research at the Chemical Dependency Institute of Beth Israel Medical Center in New York, comments that the "hardest part was trying to get information on what research was currently funded under the aegis of the NIAID," which coordinates most of NIH's AIDS Clinical Trials Group (ACTG), a network of 30 academic-based AIDS research trial centers. Many working group and panel members cite the lack of a coordinated clinical trial network as a key obstacle in the government's AIDS research effort. What's more, they contend that one of the problems in reviewing the federal AIDS program was that many of the institutes developed their own organizations to conduct clinical trials, effectively either repeating or sidestepping the ACTG program. According to Cox, "we recommended a central network that could arrange and prioritize. It will decrease duplication and give access to more patients." "For example, the National Institute of Diabetes and Digestive and Kidney Diseases is studying wasting in AIDS, and is ready to collaborate in clinical trials with NIAID," explains Lynda Dee, a member of the clinical trials panel. "There's nothing currently in place [to foster such collaborations]," notes Dee, an attorney and executive director of AIDS Action Baltimore Inc., "and little chance that institute directors would initiate that themselves." "The biggest challenge ahead is implementation," Levine states. "The first part is interpretation, of what it [the report] means and how to get it to work. I feel comfortable because the precedent is excellent at NIH" for reviewing such advisory reports and instituting recommendations. "The field is mature enough that there are scientists on the outside that should have some say in setting priorities," says TAG policy director and working group member Mark Harrington. "That's a real culture shock to NIH, though [NCI director Richard] Klausner and Varmus, as well as many scientists, are sympathetic to that view. "There aren't many things [about the report] I was unhappy with. I was pleased it was as strong as it was. Some reviews weren't as critical as I'd like them to be. The behavioral and epidemiology reviews, for example, weren't as critical as some of the others, such as vaccine. "It's not another rubber stamp [report]," he says. "But it will take a lot of pressure from the community and scientists to make sure these changes happen." Harrington will be one of those pushing the implementation process. "I'll be organizing community people on the panel and others, including advocacy groups such as the Pediatric AIDS Foundation, to work with the institutes and the OAR to help make sure this happens." Working group member Des Jarlais notes that "some money is being spent poorly, not on AIDS research, and to reallocate funds in a time of scarcity will also be difficult." He adds that some recommendations, particularly the organizational changes, will be difficult to implement. "There is also the question of who will have the power, control and authority over the budget. Will it be OAR, Harold Varmus, the institute directors?" To some, such as NIAID director Anthony S. Fauci, whose institute receives 42 percent of the AIDS research budget, the report addresses issues that aren't especially new. "For example, Dr. Varmus, Dr. Paul, and I have already been talking about the need for increasing the investigator-initiated research for some time," he notes. Likewise, he agrees on the need for a coordinated mechanism among institutes for carrying out clinical trials. Fauci, Varmus, and Paul have begun meeting with other institute directors to "examine the feasibility of implementing the working group's 14 recommendations." Fauci contends that much of the process will not be difficult because "much of it we're already doing. For example, the greater emphasis on investigator-initiated research, a new, centralized vaccine development program, more immunology research, better coordination of clinical trials-these are areas we already agreed on in principle, and were going in that direction anyway." The time line for such implementation is problematic, he notes. "Adding more money for investigator-initiated research could be done immediately, but things like a more unified structure for the clinical trials program will logistically take much longer." He doesn't see the new recommendations affecting his job of designing and implementing research. Virologist Ashley T. Haase, professor and chairman of microbiology at the University of Minnesota, acknowledges that he's glad the lengthy review is over. As part of the report's implementation, he urges "more involvement from scientists outside NIH sooner in the research process. "We need more first-rate immunologists to get involved in AIDS research," suggests Haase, who chaired the etiology and pathogenesis panel. The report recommends an OAR-sponsored series of workshops to attract new immunologists into AIDS research.

Observers Praise AIDS Report But Foresee Problems In Implementation

May 12, 1996

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