3

Elements of the NIH AIDS Research Program

In Chapter 2, the committee's main concern was to review the structures and processes for managing the NIH AIDS research program–how it is planned, implemented, coordinated, and evaluated–to ensure that all high-priority scientific questions are being addressed without gaps or overlaps, that programs are well designed and effective and efficient in achieving their goals, and that administrative support by NIH is adequate. The committee believes that these questions are especially pertinent at this time, as the program shifts to a long-term managerial mode in response to the size, complexity, and endurance of the HIV/AIDS epidemic, the large size and complexity of the NIH AIDS program itself, and the overall constraints on the federal budget. In this chapter, the committee reviews the components of the NIH AIDS research program in light of the shift to an institutionalized, long-term research effort. Where appropriate in the following sections, it offers specific conclusions and recommendations regarding the mission, design, size, and management of each component.

BASIC RESEARCH

Basic research is research that increases knowledge and understanding about basic biological processes (e.g., research in the fields of immunology, virology, or molecular biology) and causes of diseases (i.e., pathogenesis) but that may not be intended to have an immediate practical use. The NIH AIDS research program devotes a smaller proportion of resources to basic research than do most other NIH research programs. The percentage of AIDS-related basic research1 has decreased since fiscal year 1983, when basic research funding was approximately 43 percent, to its fiscal year 1990 level of 31 percent. To date, the NIH AIDS program has been more oriented toward applied research–that is, research aimed at exploiting existing knowledge and techniques to improve diagnosis and treatment as quickly as possible. Typically, institutes devote about 60 percent of their budget to basic research, through extramural grants and projects in their intramural laboratories, on the premise that in the long run knowledge gained from such research will serve as a foundation for progress in the research effort against disease.

1  

The functional categories used by the Public Health Service for classifying the AIDS budget do not allow a clear distinction between basic and applied research. For the purposes of this study, basic research encompasses the following Charlottesville functional categories: virology, etiologic agent and cofactors, immunologic studies, simian AIDS, and vaccine development.



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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH 3 Elements of the NIH AIDS Research Program In Chapter 2, the committee's main concern was to review the structures and processes for managing the NIH AIDS research program–how it is planned, implemented, coordinated, and evaluated–to ensure that all high-priority scientific questions are being addressed without gaps or overlaps, that programs are well designed and effective and efficient in achieving their goals, and that administrative support by NIH is adequate. The committee believes that these questions are especially pertinent at this time, as the program shifts to a long-term managerial mode in response to the size, complexity, and endurance of the HIV/AIDS epidemic, the large size and complexity of the NIH AIDS program itself, and the overall constraints on the federal budget. In this chapter, the committee reviews the components of the NIH AIDS research program in light of the shift to an institutionalized, long-term research effort. Where appropriate in the following sections, it offers specific conclusions and recommendations regarding the mission, design, size, and management of each component. BASIC RESEARCH Basic research is research that increases knowledge and understanding about basic biological processes (e.g., research in the fields of immunology, virology, or molecular biology) and causes of diseases (i.e., pathogenesis) but that may not be intended to have an immediate practical use. The NIH AIDS research program devotes a smaller proportion of resources to basic research than do most other NIH research programs. The percentage of AIDS-related basic research1 has decreased since fiscal year 1983, when basic research funding was approximately 43 percent, to its fiscal year 1990 level of 31 percent. To date, the NIH AIDS program has been more oriented toward applied research–that is, research aimed at exploiting existing knowledge and techniques to improve diagnosis and treatment as quickly as possible. Typically, institutes devote about 60 percent of their budget to basic research, through extramural grants and projects in their intramural laboratories, on the premise that in the long run knowledge gained from such research will serve as a foundation for progress in the research effort against disease. 1   The functional categories used by the Public Health Service for classifying the AIDS budget do not allow a clear distinction between basic and applied research. For the purposes of this study, basic research encompasses the following Charlottesville functional categories: virology, etiologic agent and cofactors, immunologic studies, simian AIDS, and vaccine development.

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH National Institute of Allergy and Infectious Diseases–NIAID finances the largest portfolio of AIDS-related basic research of all the NIH institutes. NIAID's basic research goals are to examine HIV entry mechanisms, cell types (host and virus), reservoirs, and latency; study the mechanisms of cellular immunity; assess the role of autoimmunity in AIDS pathogenesis; research the role of other viruses as cofactors in AIDS; understand HIV gene regulation; define the viral components responsible for infectivity, syncytia formation, CD4 receptor binding, and immune response elicitation; and determine the mechanism of T-cell killing. NIAID's AIDS-related basic research is conducted in many venues, including universities, independent laboratories and research centers, and its intramural laboratories. The Pathogenesis Branch in NIAID's Division of AIDS (DAIDS) administers most of the institute's AIDS basic research grants. Its mission is “to discover the mechanisms by which HIV causes immune deficiency, produces other pathological disorders, and avoids immune surveillance” (NIAID, 1990). The branch's extramural grants support research on the biological properties, molecular biology, and host response to HIV infection and on the development of an animal model for HIV infection. The branch administers Programs of Excellence in Basic Research on AIDS (PEBRA), which are five-year grants to support clusters of long-term investigations of biological processes related to AIDS. PEBRAs were awarded to five sites in 1988. DAIDS also funds nine centers for AIDS research using core grants to investigators who have a record of proven excellence in AIDS research and are already receiving NIH funds. The grants provide core support for central research and support services and also include some money for salaries for junior-level investigators and for renovation and upgrading of facilities. Intramurally, NIAID's researchers are conducting a range of research on the nature of the etiologic agent (HIV) and its pathogenesis in addition to a considerable program of vaccine and drug development studies. Selected research includes studies focused on the immunopathogenic mechanisms of HIV infection and opportunistic infections, animal retroviruses, and how the CD4 receptor recognizes the HIV envelope protein. National Cancer Institute–NCI supports the next largest basic AIDS research program at NIH, much of it intramural. Its efforts focus on HIV and the mechanisms of pathogenesis, including the following major areas: regulation of HIV gene expression, the mechanism of HIV infection, virus cofactors in pathogenesis, regulation of the CD4 receptor, mechanisms of loss of T-helper cell immune function, processing of HIV proteins, the role of cytokines and immunity in HIV pathogenesis, and research on the structural biology of HIV for the purpose of devising therapeutic agents. National Institute of Neurological Disorders and Stroke–NINDS supports the third largest NIH program of basic AIDS research, the primary goal of which is understanding the relationship between HIV and the human nervous system. NINDS-supported research falls into two main scientific areas: how HIV damages nervous system cells and how it crosses the blood-brain barrier. In support of these research endeavors, NINDS funds both extramural and intramural basic research. Extramural research focuses on HIV subtypes that enter the brain, methods to improve the transport of drugs into the central nervous system, and the role of metabolites in the pathogenesis of AIDS dementia. In contrast, intramural research examines a number of key scientific questions including SIV neurologic disease, analysis of the effect of HIV gene products on nervous system cells, the pathogenic mechanism of AIDS dementia, and differentiation of HIV-and zidovudine (AZT)-induced neuropathies. National Heart, Lung, and Blood Institute–NHLBI conducts a wide range of AIDS research from the very basic to the clinical, focusing on the cardiac, pulmonary, and hematologic consequences of HIV infection. The institute's basic AIDS research includes the following major areas: chronic processes of cardiac and pulmonary pathology in AIDS, HIV-related viruses, the pathogenesis of cardiac and respiratory problems unique to the pediatric population, the HIV disease process in the lung (particularly to understand cell injury caused by Pneumocystis carinii

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH pneumonia), the pathogenesis of cardiac complications, and the causes of the numerous blood deficiencies induced by HIV infection. Despite the support by the above institutes of basic science research related to HIV infection, many critical gaps remain in current understanding of the basic biology of HIV and its associated opportunistic infections and cancers. The committee notes that most of the progress in understanding and treating HIV infection and related diseases has been based on knowledge generated from basic, undifferentiated research that predates the advent of the AIDS pandemic. To date, the NIH AIDS research program has emphasized directed research, primarily in large-scale collaborative studies, in an effort to develop a quick cure from existing knowledge. It is now evident that a cure or vaccine is years away and that their development will come from a better basic understanding of HIV infection and pathogenesis. The committee believes that a strong basic research program is critical in supporting such applied activities as drug and vaccine development. Basic research on HIV and the disease it causes will in turn produce new knowledge and methods that may contribute to progress against other diseases. Recommendation 3.1: Greater investments should be made in basic research in such areas as immunology, virology, and molecular biology as part of NIH's long-term research program on AIDS. These basic research advances are critical not only to progress against AIDS but also as a contribution to the base of fundamental knowledge that will be needed to deal with other diseases of the present and future. VACCINE RESEARCH AND DEVELOPMENT As recently as early 1989, many AIDS researchers expressed considerable pessimism about the possibility of developing an effective HIV vaccine. In the past year, however, a more hopeful outlook about vaccine development has begun to prevail, largely based on some recent successful experiments with rhesus macaques. SIV and the infection it causes in rhesus monkeys constitute a valuable model for HIV and AIDS. For example, the SIV genome is similar in organization to that of HIV, and, like HIV, the simian virus also infects host cells through their CD4 surface receptor. In addition, infection is persistent and eventually leads to T-cell immunodeficiency with an AIDS-like syndrome and death. Two recent trials of immunization of rhesus monkeys with formalin-fixed whole killed SIV have led to a substantial level of protective immunity against the virus. Although crude, inactivated whole virus may not be the final acceptable form of the vaccine because of its risks (i.e., virus inactivation approaches 100 percent but generally leaves residual trace amounts of infectious material), its demonstrated effectiveness provides a valuable target for systematic comparison with various purified HIV antigens and synthetic epitopes. Further systematic exploitation of the SIV-rhesus monkey model may bring additional progress. Although recent developments give considerable cause for optimism about the prospects for an HIV vaccine, the difficulties that must be overcome remain formidable (Bolognesi, 1989). The critical components of an HIV vaccine, as well as the relative importance of humoral versus cellular immunity, have yet to be determined. There is still no agreement on the clinical goal of a vaccine. Should it completely block infection? Prevent disease? Or delay the onset of disease? Answers will probably come from empirical approaches in which vaccines that elicit powerful antibody or T-cell responses will be tested on various populations under diverse conditions. The available animal models are still limited. Chimpanzees can be infected with HIV but do not develop disease; rhesus monkeys, on the other hand, develop an AIDS-like disease from SIV

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH but are unaffected by HIV. The SCID-hu mouse shows some promise as a model for testing new drugs, but it has not yet been shown to respond immunologically to HIV antigens. A major obstacle to tests of the efficacy of any HIV vaccine is the lack of consensus on specific immunologic end points that correlate with immunity. Should the end point be the production of neutralizing antibodies? Other antibodies? CD4 T cells? Or CD8 T cells? The consequences of HIV genetic variation on immunologic responses have not been thoroughly evaluated, although they may render a vaccine ineffectual in some patients. From general experience with experimental and clinical vaccines it is clear that one or more adjuvants2 are likely to be critical components of an HIV vaccine. The mechanism of action of adjuvants is still far from clear, however, and only a few of them are available for use in humans. Overcoming these obstacles and taking advantage of the opportunities presented by recent successes will require a concerted effort by all sectors involved in vaccine research and development. The following sections describe the NIH vaccine program and propose a role for NIH in the overall scheme of HIV vaccine development. NIH Vaccine Research Program In fiscal year 1990, NIH allocated $78.6 million for HIV vaccine-related research; the fiscal year 1991 budget projects a 10 percent increase in that amount, bringing the total to approximately $86.1 million. The bulk of NIH vaccine research is sponsored by NIAID and NCI. National Institute of Allergy and Infectious Diseases NIAID's Vaccine Research and Development Branch (VRDB) located in the Division of AIDS acts as NIH's primary arm for planning and funding vaccine research. The President's 1990 budget allotted $51.2 million to NIAID for vaccine research; of that amount, the VRDB received $32.1 million for 1990 with the remainder divided among intramural research and research support contracts. The VRDB is divided into three sections that span basic research, preclinical science, and clinical testing. Through each of these sections, NIAID funds a variety of grants, cooperative agreements, and contracts for extramural vaccine researchers. NIAID officials identified several major VRDB efforts: identifying gaps in AIDS-related basic immunology research in order to target program resources; developing a preclinical capacity in extramural locations for testing candidate agents in vitro and in animal models; developing a capacity for assessing vaccines in human trials; continuing coordination with WHO so that once there is a promising candidate, phase 3 efficacy trials can begin as soon as possible; and monitoring the progress of candidate HIV vaccines through preclinical testing and evaluating selected vaccines in phase 1 and 2 trials at the AIDS vaccine evaluation units supported by NIH. 2   An adjuvant is a substance that enhances the effectiveness of a medical treatment; in immunology it is generally a nonspecific stimulator of the immune response.

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH NIAID's basic research program consists largely of a mixture of grants and contracts that support extramural investigators in studies of the role of HIV genetic variation, the immunology of a protective response, and lentiviruses in a variety of animal models. NIAID' s preclinical development section constitutes the core of its vaccine efforts. In this area, NIAID funds 11 national cooperative vaccine development groups (NCVDG), each of which is a consortium of industry and academic scientists that collaborate on preclinical vaccine development –for example, immunologic research, evaluation in animals, and production of reagents needed to conduct human trials. For example, the NCVDG program funds the two primate centers in Boston and New Orleans that recently demonstrated successful protection by a whole-killed-SIV vaccine in macaques. The fiscal year 1990 funding for the NCVDG program is $13.2 million. In addition to the NCVDGs, the preclinical section funds 16 cooperative groups that study HIV vaccine adjuvants and supports an HIV vaccine repository program to provide quality-controlled reagents to any NIH-sponsored researchers. In early 1990 NIAID's clinical development section awarded five-year contracts to five AIDS vaccine evaluation units (AVEU), four of which already have a long record of testing vaccines for various infectious diseases. All five of the AVEUs have experienced investigators on staff who are capable of conducting phase 1/2 testing of candidate HIV vaccines. AVEUs are an important component of NIH's vaccine program that provide a capability to conduct early clinical testing of vaccines on a small number of patients. The NIAID clinical section also supports the AIDS Vaccine Selection Group of senior scientists charged with setting guidelines for trial eligibility of candidate vaccines and recommending which candidates NIH should evaluate. National Cancer Institute NCI recently established the AIDS Vaccine Task Force, which is pursuing the development of an effective AIDS vaccine. In 1991 NCI will receive approximately $19.1 million for vaccine research, most of which supports intramural studies in two areas: identifying HIV peptides that can raise a protective immune response and determining how to combine synthetic peptides to produce a more effective vaccine than one based on a single HIV protein. NCI researchers favor the combined peptide approach because of the possibility of transmitting infectious particles in a whole-killed-virus vaccine. The Role and Mission of NIH Until now, NIH's primary functions have been to fund investigator-initiated extramural and intramural research, develop reagent and animal model resources, and promote information exchange among researchers. Each of these functions is valuable and well suited to NIH's traditional role of facilitating scientific research, but the recent breakthroughs in vaccine studies have raised the question of whether NIH should invest additional resources in vaccine research and assume a greater role in coordinating its next stage. The committee believes NIH can make significant contributions in vaccine research that would complement efforts in the private sector by continuing to identify research needs and provide research resources, continuing to facilitate scientific exchange among researchers, increasing its support of basic science research, and increasing its leadership role for the planning of trials of vaccine candidates. Therefore, NIH should increase the scale of its vaccine research program and define a clear mission that is coordinated with ongoing efforts in industry and in the academic and international sectors.

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH As previously discussed, the field of vaccine research is progressing rapidly, yet many scientific obstacles remain to be resolved before an effective HIV vaccine can be developed. The committee commends NIH's funding of a wide range of research approaches but notes that the lack of new NIH resources for extramural research has prevented qualified investigators outside of the ongoing NCVDGs from acquiring NIH support. Given the large number of scientific opportunities and the availability of investigators, the committee believes NIH should expand its funding to support investigators able to address the most pressing questions in the search for a vaccine against HIV/AIDS. Increased support of investigator-initiated research can make a significant contribution to overcoming the scientific obstacles that stand in the way of a vaccine against AIDS. Given the tremendous public health benefits of an effective vaccine, it is important to pursue as many promising research avenues as possible, including those that may not be fully explored or that may be bypassed by traditional investigator-initiated funding mechanisms. To pursue research opportunities adequately, the committee believes that an increase in RFAs and RFPs is appropriate. Recommendation 3.2: NIH should expand its vaccine research program and furnish strong support for agents that show promise of efficacy and for requests for applications and requests for proposals that target the essential unanswered immunological questions. The committee considered and rejected recommending a centralized approach to vaccine research, that is, a centrally directed, narrowly focused program that would devote a large amount of money to bringing together the major vaccine researchers and conducting a coordinated attack on the essential questions in AIDS vaccine research. Researchers interviewed by the committee were divided in their views of the wisdom of a centralized program. In its support, several NIH officials emphasized the need for rapid performance of the critical experiments required to follow up the recent SIV studies and their view that NIH was the only institution capable of assembling all of the researchers necessary to develop and execute a coordinated plan. They also noted that a more directed approach would increase data sharing among researchers, lessen the risk of duplication, and encourage pooling of limited reagents and resources. Extramural vaccine researchers argued that central planning would not work at this stage because scientists lack the base of knowledge needed to plan a centralized approach; in particular, agreement is lacking on a limited number of specific questions as the top priorities for investigation. The committee believes that a centralized approach to HIV vaccine development would be warranted when experts in this field reach near-unanimous consensus that only a few clearly defined research questions stand in the way of developing a vaccine. As there is presently no such consensus, the committee believes it necessary and appropriate for NIH at this point to pursue a wide range of scientific leads. Interviews with NIH officials indicated that NIAID and NCI, the two lead institutes at NIH for vaccine research, run relatively independent research programs with different scientific priorities. NIAID has put substantial resources into expanding the SIV model on the hypothesis that whole-virus research is essential groundwork for development of an effective human vaccine. NCI research, on the other hand, concentrates on identifying specific subunit epitopes of HIV that may confer protection. As with many other aspects of the NIH AIDS research program, the committee believes that expertise and input from multiple institutes strengthen the vaccine research program. The relative lack of direction within NIH vaccine research is also consistent with the agency's traditionally decentralized approach to research. In this case, however, the committee is concerned that the two institutes' efforts are inadequately coordinated, which may lead to the inefficient use of scarce resources.

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH Recommendation 3.3: NIH should create an agencywide vaccine research advisory panel of top extramural scientists to identify research needs, establish priorities, and determine the resources and facilities required for a successful program. In addition, the panel should perform an oversight function to ensure that institutes supporting diverse lines of SIV and HIV research use resources effectively and in a complementary manner. The committee further recommends that this advisory panel outline a mission for NIH's AIDS vaccine research that complements vaccine research being conducted by the pharmaceutical dindustry. Many NIH and pharmaceutical industry representatives interviewed for this study asserted that drug manufacturers' liability concerns about developing an HIV vaccine, particularly whole-killed-virus types, have slowed some areas of vaccine research. Some observers believe that these liability fears may be a deterrent to industry vaccine development. NIH, on the other hand, as a component of the federal government, has a responsibility to advance as many promising vaccine approaches as possible, despite legal or financial concerns. In its history, NIH has often taken on scientific tasks that offer little incentive to pharmaceutical companies; one example is NCI 's cancer clinical trials program of combination drug regimens that appear to have a public health benefit but offer little financial promise to the pharmaceutical industry. Because of the liability issues surrounding whole-virus vaccine research, the committee believes NIH could serve the public interest and contribute greatly to an understanding of protective immunity by increasing its support of research in this area. In addition to liability concerns, when and if attractive candidates for vaccines emerge, the clinical trials that must be conducted to establish their efficacy will be logistically difficult (IOM/NAS, 1988:145). One unresolved dilemma centers on developing criteria for placing an HIV vaccine candidate into human efficacy trials. Another major problem involves potential trial populations. The trials will have to enroll sufficiently large numbers of subjects at sufficiently high risk of infection that any decrease in the number of infected persons attributable to the experimental vaccine will be statistically significant. (For this reason, the sites for large-scale efficacy trials will most likely include African and other developing countries.) For ethical reasons, those who receive the vaccine must be counseled about behavior changes that reduce the risk of HIV infection, which will increase the number of trial participants required. The deliberate seroconversion of seronegative individuals will also raise difficult ethical issues. The committee notes that NIAID's Vaccine Research and Development Branch has begun to address the issues surrounding deliberate seroconversion, and it commends these efforts. Recommendation 3.4: NIH should begin immediately to plan the trials (especially phase 3) that eventually will be required to test a viable vaccine candidate. This process should include the development of criteria for entering a vaccine candidate into human efficacy trials. The committee further recommends that NIH work with Congress to evaluate plans to provide liability coverage for the development of vaccines that pharmaceutical companies otherwise may hesitate to evaluate. Confronting AIDS: Update 1988 (IOM/NAS, 1988) noted that the development of a small, well-understood animal model, such as the mouse, would greatly enhance vaccine development. The committee is particularly concerned that NIH does not support adequate facilities for the growing number of animals needed for vaccine testing; this shortage continues at present despite agency officials' assertions that increased isolation and holding space in primate facilities are critical to preventing further delays in research. The committee believes NIH needs to provide funding

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH for new facilities with suitable containment areas (rated at biosafety levels 2 and 33) for its own campus and for extramural academic sites, which would enable expanded use of potential animal models such as the rhesus monkey and SCID-hu mouse. The long lead time necessary for breeding animals highlights the urgent need to plan ahead for adequate resources so that when a candidate vaccine is ready for preclinical testing, scientific progress will not be hindered by inadequate supplies of animals, substandard facilities, or unavailable reagents. Recommendation 3.5: NIH should provide the support needed to ensure an adequate supply of nonhuman primates, especially chimpanzees and rhesus monkeys, for preclinical development and testing of HIV and SIV vaccine candidates. NIH should also pursue the development of other animal models that might be cheaper and easier to use in vaccine development. Finally, through the associate director for AIDS research, NIH should coordinate the research plans of the various categorical NIH institutes investing in vaccine development with the long-term plans of the National Center for Research Resources for developing and supporting animal models. NIH officials and extramural researchers were unanimous in asserting that poor access by investigators to quality-controlled reagents has hindered HIV vaccine research. Reagents that were identified as particularly important were supplies of purified HIV proteins, various strains of SIV, and T- and B-cell lines. NIH officials reported that extramural researchers frequently do not share reagents they have developed with NIH grants because such sharing may lessen the credit given for the original finding. The committee believes NIH has a responsibility to ensure that reagents developed with NIH funds are made available to the entire scientific community. The committee commends NIAID's efforts to establish a reagent repository program for vaccine research as an excellent example of how NIH can facilitate the research process from a neutral position. Recommendation 3.6: NIH should strongly support a full-scale reagent repository and implement the recommendation from Confronting AIDS: Update 1988 that “all investigators receiving NIH funds must make their AIDS-related reagents available to a distribution center, and thereby to all qualified investigators, after publication of their research.” NIH should enforce this policy by making further funding contingent on cooperation with a reagent pooling program. EPIDEMIOLOGICAL RESEARCH NIH conducts epidemiological research to improve understanding of the natural history of HIV infection, which aids the development of treatments and vaccines for HIV disease. Natural history studies seek to describe the sequence of clinical manifestations and biological processes that occur throughout the course of infection; these studies provide the foundation for a range of other AIDS research efforts at NIH, including clinical trials of therapeutics and vaccines and development of clinical practice guidelines. Within NIH, nine institutes support epidemiological studies on AIDS and HIV infection (Table 3.1), with each institute sponsoring studies related to its particular mission. The sections below briefly discuss these programs. Total funding for NIH-supported HIV-related epidemiological 3   A summary of biosafety level definitions and recommendations of the Centers for Disease Control and the National Institutes of Health may be found in the April 1, 1988, Morbidity and Mortality Weekly Report, Vol. 37 (suppl. S-4).

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH research in fiscal year 1990 was approximately $125 million, or about 17 percent of NIH's AIDS budget. National Institute of Allergy and Infectious Diseases NIAID studies account for more than half of NIH's AIDS epidemiology budget. Among NIAID's major initiatives are four large, prospective natural history studies of HIV infection: the Multicenter AIDS Cohort Study (MACS), the San Francisco Men's Health Study (SFMHS), the Women and Infants Transmission Study (WITS), and the Heterosexual HIV Transmission Study (HATS). The MACS is a prospective study of HIV infection that follows more than 4,000 homosexual male volunteers every four to six months to assess virologic, immunologic, clinical, behavioral, and neurological status. The SFMHS is a prospective study of the natural history and epidemiology of HIV infection in a cohort of 1,034 single men aged 25–54. Unlike the MACS, participants were recruited using a population-based sampling strategy, which results in the inclusion of both homosexual and heterosexual men. The WITS, a collaborative effort with NICHD, investigates the effects of HIV infection on pregnant women, perinatal transmission, the impact of pregnancy on the course of HIV infection, and pediatric outcomes. HATS examines factors related to HIV transmission in persons without histories or evidence of male homosexual behavior or intravenous drug use, and in couples discordant for HIV status (i.e., one partner is infected and the other is not). NIAID also collaborates with the U.S. Army on the Newark Perinatal Study, which involves women at risk for HIV infection, and maintains a specimen repository as a resource for its other studies. A range of internationally focused epidemiology studies are another aspect of NIAID's epidemiological program. The institute initiated collaborative efforts with the Pan American Health Organization to facilitate the development of epidemiological research in Latin America and the Caribbean on HIV and associated infections. NIAID also supports the International Collaboration for AIDS Research program, which provides research grants to U.S. universities to foster collaborative epidemiological studies with investigators in foreign countries (currently, Uganda, Mexico, Brazil, Malawi, and Zaire). The third major international initiative is Project SIDA. This project supports a series of epidemiological, clinical, and laboratory science studies in Kinshasa, Zaire; prospective studies there include workers, women and children, and couples. National Heart, Lung, and Blood Institute NHLBI sponsors epidemiological studies focusing on transfusion safety and the identification of HIV in blood products. It also sponsors several major studies that have made significant contributions to an understanding of HIV prevalence and transmission. For example, the Transfusion Safety Study established in 1983 is a multicenter study to evaluate factors that influence the risk of transfusion-associated AIDS. A study of human retroviruses in volunteer blood donors, another NHLBI effort, examines the prevalence of retrovirus seropositivity in first-time blood donors, the rate of retrovirus seroconversion in repeat blood donors, and risk factors for antibody-positive donors. In their study of the effectiveness of screening for retroviruses, NHLBI researchers are evaluating the effectiveness of present screening efforts to identify HTLV-I, HTLV-II, and HIV in infected whole blood units, blood components, and Factor VIII concentrates. The institute has also established the Serum Repository, which seeks to facilitate the identification of seropositive donors and of recipients of blood products from these donors.

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH National Cancer Institute NCI supports HIV-related epidemiological research to generate and test hypotheses about the role of pathogenic human viruses in the etiology of cancer and to expand the AIDS epidemic knowledge base, focusing on cancer in particular. To this end the institute supports a broad range of efforts, including large and modestly sized prospective studies, collaborative studies, and an international registry. Among NCI's largest initiatives is a study of hemophiliacs and their female sexual partners, which involves a multicenter cohort (16 domestic and 4 foreign sites) of 1,219 subjects with hemophilia or related disorders. The study is both retrospective and prospective and designed to define rates, markers, and cofactors of HIV infection and AIDS. It uses samples from NHLBI's hemophilia centers, which were established and operational prior to the HIV epidemic. A study of parenteral drug users, conducted in collaboration with the National Institute on Drug Abuse, evaluated 1,766 parenteral drug users for HIV and HTLV-I and HTLV-II infection. In 1982, NCI established a cohort of 249 gay men, recruited from the New York City and Washington, D.C., metropolitan areas. At the time of its initiation, this study was unusual in that it focused on the cohort rather than the disease. In a study of mothers and infants, a collaborative effort with NICHD, researchers are examining the effects of HIV infection on pregnancy, the factors associated with vertical transmission, and the effect of HIV disease on the health status of the newborn. In a prospective study of heterosexual transmission of AIDS, spouses and long-term partners of patients in various clinical stages of HIV infection are being studied to gain a better understanding of risk factors for acquiring HIV and its sequelae; both behavioral and serologic factors are considered. (Children of the index cases [i.e., the infected individuals] are also enrolled in the study.) To study the relationship between AIDS and cancer, in particular, Kaposi's sarcoma, and identify risk factors, researchers are analyzing a case-control study of homosexual men with the condition recruited from New York City. NCI has established an international registry of persons with AIDS who have documented dates of HIV seroconversion to evaluate cofactors and trends in risk for HIV infection. Thirty-eight investigators from three continents have contributed 1,115 subjects for analysis. National Institute of Child Health and Human Development NICHD conducts several epidemiological and natural history studies related to HIV, as well as research on associated risk factors in pregnant women, mothers, infants, children, and adolescents. Its perinatal natural history study focuses on the neurodevelopmental outcomes of children exposed to and infected with HIV. The study is conducted at three centers and is a component of the collaborative NICHD/NCI study on vertical transmission noted above. NICHD also collaborates (by means of interagency agreements) with the Department of Defense in a study of the epidemiology of HIV among pediatric and perinatal patients from military families. Additional research includes a study of the natural history of HIV infection in hemophiliac children. This investigation is a multicenter study of 263 children conducted in collaboration with the Office of Maternal and Child Health of the Health Resources and Services Administration, which funds a network of comprehensive health centers for hemophiliacs. The study compares developmental, neurological, and immunologic outcomes of HIV-infected hemophiliac children with outcomes of uninfected hemophiliac controls and uninfected male siblings. Finally, an NICHD-sponsored seroepidemiological study of HIV prevalence among childbearing women uses routinely

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH collected, paper-absorbed samples of newborn blood to examine trends in HIV infection among women. The study gathers data on about 80,000 births per year in the northeastern United States and North Carolina. Fogarty International Center A collaborative effort by the Fogarty International Center (FIC) and NIAID established the International Network for AIDS Research and Training, which links the major international AIDS programs of NIH, the Centers for Disease Control, the U.S. Agency for International Development (USAID), the World Health Organization's Global Programme on AIDS, and the Pan American Health Organization. The network is intended to facilitate the coordination of research and training needs, identify emerging research opportunities and appropriate responses, and minimize duplication of effort among NIH institutes and between U.S. organizations and the programs of other governmental and international organizations. Other NIH Epidemiological Studies Studies supported by the remaining four institutes–the National Institute of Dental Research (NIDR), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute on Aging (NIA), and National Center for Nursing Research (NCNR)–account for less than 3 percent of the NIH HIV epidemiology budget. Each institute supports initiatives related to its mission: NIDR supports research on the oral complications of HIV infection, NIAMS studies skin disorders associated with HIV infection, NIA investigates the prevalence of HIV in the over-50 population, and NCNR conducts studies on the nursing needs of HIV-infected persons. Results Information provided by NIH-sponsored epidemiological studies includes the following: NHLBI's Transfusion Safety Study provided definitive evidence that HIV is not transmitted by casual but rather by sexual contact with infected persons and from infected mothers to their babies. Data gathered by the MACS showed a marked increase in the risk of contracting Pneumocystis carinii pneumonia (PCP) when an individual's CD4+ cell count dropped below 200 per cubic millimeter (mm3) of blood. This information became the foundation for the Public Health Service's recommendation that HIV-infected persons with CD4+ cell counts below 200/mm3 receive prophylactic therapy against PCP. A neuropsychiatric substudy of the MACS demonstrated that neurologic or psychiatric complications of HIV infection are rarely seen prior to the onset of other HIV-related symptoms. This information refuted earlier assertions that neuropsychiatric deterioration may be among the first manifestations of HIV infection. The SFMHS, studying neutralizing antibodies to HIV, demonstrated that a patient's ability to neutralize his or her own HIV isolates does not correlate with the progression of HIV infection.

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH Recommendation 3.21: The committee believes NIH should increase participation of presently underrepresented populations (i.e., minorities, current and former users of intravenous drugs, women, and children) in AIDS drug trials. To achieve this goal, NIH should (1) examine entry criteria for clinical trials and, where appropriate, make them less stringent, and (2) improve outreach and the provision of ancillary services to underrepresented populations. Coordination NIH has conducted pediatric AIDS trials at three different institutes (NCI, NIAID, and NICHD), each of which has made important and different contributions to clinical research on pediatric AIDS. Since 1986, the NCI intramural program has performed studies on AZT, ddI, and ddC that showed a beneficial effect of nucleoside agents in children; it continues to perform phase 1 studies on single and combination antiviral therapies in children with AIDS and HIV infection that will lay the groundwork for multicenter phase 2/3 efficacy trials. In 1987, NICHD created an extramural clinical trials network to evaluate the efficacy of intravenous immunoglobulin (IVIG) in reducing the incidence of bacterial infections, thereby bringing experimental therapy to patients in 27 clinical centers and urban hospitals who had no other access to it. Although there has been much controversy over the scientific value of this trial, it has served to focus attention on the question of IVIG efficacy, which was a legitimate scientific concern, as well as on pediatric and maternal AIDS, which had received very little attention from NIAID. Currently, NIAID has 15 pediatric ACTUs within the ACTG that have assumed responsibility for conducting phase 1 studies and phase 2/3 pediatric trials. The ACTUs provide a large cadre of experienced investigators and scientific resources. In addition, the pediatric core committee of the ACTG has taken a leading role in articulating a scientific agenda for pediatric clinical research. The committee believes that the use of three separate institutes for a common purpose has brought a wide variety of expertise and resources to bear on pediatric AIDS research, and it commends the efforts of each. But the pediatric trials are also a prime example of NIH's need for an oversight mechanism capable of resolving interinstitute disputes and implementing necessary corrective changes. Most noticeably, NIAID and NICHD have each maintained clinical trials systems (that together total 43 sites) for nearly three years without significant collaboration (many of their sites overlap in the same urban location); they continue to operate their networks through separate management and funding mechanisms. In late 1989, the associate director for AIDS research at NIH directed the NICHD trial system to merge with the ACTG, thus creating a single coordinated network for testing drugs in children. Interviews with NICHD and NIAID officials in mid-1990, however, indicated that the two systems had not yet achieved a functional union. Thus far, the ACTG has incorporated NICHD investigators on its pediatric core committee, but the central management and financing of the two systems remain distinct. (NICHD continues to administer its own contract and use a different data center.) The committee believes that an operational merger of the NICHD and NIAID systems is highly unlikely as long as the institutes operate them independently and there is no authoritative mechanism in place to resolve conflicts and produce a functional unity. The committee is concerned that interinstitute conflict may have hindered NIH's ability to design efficient clinical trials involving children and pregnant women and to enroll as many

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH individuals as possible in them. NICHD and NIAID can each make valuable contributions in a multidisciplinary approach to clinical research on maternal and pediatric AIDS. For example, the NICHD system enlists many pediatricians and obstetricians who are sensitive to the needs of mothers and children living with HIV infection; in addition, the NICHD trial sites have access to many patients who are not now available to the pediatric ACTUs. The committee believes NIH can best capitalize on its pediatric trial resources by ensuring that all ACTG trials are accessible to patients at NICHD sites. The committee recognizes that NICHD and NIAID face financial constraints in merging their systems but believes that the importance of pediatric AIDS research justifies the costs. Recommendation 3.22: NIH should complete the merger of the NICHD and NIAID pediatric trials systems to unify their management and funding and ensure maximal use of the two institutes' resources. The merger should include sufficient funding to allow enrollment of NICHD's large pool of patients. Besides the extramural ACTG program at NIAID, several other NIH institutes or institute components conduct AIDS clinical trials that test therapeutic agents for HIV disease. Indeed, the intramural programs at NCI and NIAID possess resources that have allowed them to achieve important advances in the development of new AIDS therapies. For example, the NCI pediatric branch has made a major commitment to perform AIDS trials without any increase in staffing or space and has played an integral role in the evaluation of drugs for the treatment of children with AIDS and HIV infection. The committee commends NCI's commitment and believes NIH should provide the NCI pediatric branch with increased resources to ensure that its AIDS efforts do not compromise the work of the institute's Pediatric Oncology Branch. NCI's adult clinical trials program has as its primary mission the transfer of preclinical lab findings into phase 1 studies that can assign priorities to new agents for larger efficacy trials. NCI scientists assert that the close proximity of their lab and clinic allows them literally to bring agents across the hall from the lab for testing in humans. The connection between lab and clinical trials promotes rapid in vivo testing of in vitro results, an important factor in NCI's considerable success in conducting studies on anti-HIV drugs. In addition, numerous NIH officials noted that the NCI and NIAID intramural programs benefit greatly from the relative autonomy of their operations. The intramural scientists work at a single site with a small nucleus of experienced people. They write their own protocols, negotiate directly with drug sponsors to obtain therapeutic agents, and conduct informal talks with the FDA about IND and trial design issues. NIH intramural officials say that, because of their autonomy and the fact that intramural trials are predominantly small phase 1 trials, the testing process–from the origin of a trial concept to initial accrual of participants–occurs in two to four months. The intramural programs also provide comprehensive care for patients participating in the trial, including all health care costs, psychological support, and transportation expenses. These services, as well as onsite intensive education of staff and patients about how to follow complicated protocols, ensure a high rate of compliance for intramural studies. Recommendation 3.23: NIH should continue to provide strong financial support for AIDS research efforts of the intramural clinical trials programs. In fiscal year 1990, NCI received $35.4 million for its intramural AIDS clinical trials (both the pediatric and adult programs). This amount was approximately 22 percent of NIH's total 1990 AIDS clinical trials funding of $164.5 million. The committee believes that the NCI intramural program has provided many important results related to the clinical evaluation of AIDS drugs, most notably its phase 1 studies of AZT, ddI, and ddC. The committee notes that the productivity of

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH the NCI program reflects the effective coordination of NCI's preclinical and phase 1 resources and NCI's efforts to ensure larger-scale testing of its drugs in the ACTG or by the pharmaceutical industry. Some NIH officials have expressed concern that NIH does not have a single track for bringing a drug through all stages of clinical testing. The committee recognizes that the many clinical trial resources at NIH and in the private sector offer the strengths of diversity and differing expertise. Nevertheless, NIH needs to assign responsibility more clearly for each step in the clinical evaluation of a new AIDS drug, taking into account the varying strengths of each trial resource. For example, several NIH officials interviewed for this study noted that the NIAID intramural program was underused for conducting phase 1 trials on novel anti-HIV drugs. These officials added that the ACTG did not routinely send new drugs for testing to the intramural program despite the ACTG's high number of prospective protocols and the available resources of NIAID's intramural program. Recommendation 3.24: NIH should establish a mechanism for better coordination of extramural and intramural clinical trials and consider shifting more responsibility for phase 1 studies to the intramural program. Information Dissemination The extreme sense of urgency surrounding the results of AIDS clinical trials has placed great pressure on the agency to obtain and release usable trial data quickly. In turn, the mode of release of AIDS trial results, which is more rapid than for any other trials NIH has ever conducted, has generated much controversy in the past year, with the debate centering around the timing, forum, and clinical applicability of the released results. The committee believes NIH should ensure publication of all results of its clinical trials, whether the trial has a positive, negative, or indeterminate conclusion. In addition, all basic data generated in the trials should be made available because the publication process is the primary means for expanding a widely available knowledge base. Yet the results of many ACTG trials, results that include considerable data that NIH has publicly offered as ACTG accomplishments, remain unpublished. Only 4 of 27 ACTG accomplishments announced by NIAID in May 1990 had been published in a scientific journal; missing from public access were several sets of results that had a direct impact on clinical regimens being followed by many patients. Customarily, NIH-sponsored investigators take several months to synthesize their data, write a complete report, and send it to a scientific journal for peer review and, ultimately, publication. In the field of AIDS, however, NIH officials, practicing physicians, and the patient community agree that ACTG trial results often are too important to delay their release for the six to nine months often required for standard journal publication. The committee strongly endorses the use of expeditious peer review and publication as the best method of information dissemination; it recognizes, however, that alternative, faster means may be needed for certain clinically relevant results, although the process must be managed with concern for all affected parties. For example, in the case of ACTG trials 016 and 019, which documented benefits from the early use of AZT, NIH held a press conference to announce a summary of the trial results but made no recommendations on changes for clinical practice. Using a press conference to release data without accompanying clinical recommendations left many community physicians and patients extremely uncertain about the practical significance of the results. The committee recognizes that the high profile of ACTG trials may continue to require the use of press releases, but it strongly criticizes the use of communication through the media as a primary means of dispersing information and

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH believes that such dissemination of trial results does a disservice to patients and practicing physicians. The committee recognizes the substantial controversy that surrounds the question of early publication of trial results. On one hand is the understandable desire of ill persons to find rapid answers and guidance from clinical trials; on the other is the desire of researchers to ensure that their conclusions are accurate and reliable. A balance must be struck between the risks of rapid release (i.e., findings that later prove to be incorrect, incomplete, or harmful to patients) and its potential benefit. The committee believes it important to release trial results as quickly as possible; however, it also believes that released data and conclusions that are not carefully and thoughtfully considered benefit neither patients nor scientists, and do not contribute to the knowledge base. Therefore, the committee recommends that NIH establish a mechanism to ensure an element of expedited peer review before the dissemination of trial results. Recommendation 3.25: The ACTG should institute a comprehensive policy requiring submission of trial data to a peer-reviewed journal within a specified time after completion of the trial or a major protocol change, and timely submission of results should be linked to ACTU evaluations. In addition, NIH should develop a mechanism for public reporting of data with clinical urgency soon after trial completion and prior to journal publication. Some concerns have been raised that the early release of trial results might lessen the imperative felt by investigators to publish full scientific papers in peer-reviewed publications. An interim publication in no way lessens NIH's responsibility and that of its investigators to publish their data in full. Recommendation 3.26: The ACTG should establish a working relationship with scientific journals to ensure rapid interim and full publication of high-priority trial results. RESEARCH RESOURCES As a public good for which federal support is especially suited, research resources are investments in the infrastructure of biomedical science that help researchers do their work economically and quickly. Their importance increases as the epidemic becomes endemic and the AIDS research program settles into a long-term effort. NIH supports a number of research resources programs through the AIDS budget, including (1) training grants; (2) animal models, such as the regional primate centers and the national chimpanzee and macaque monkey breeding and research programs; and (3) grants for building or upgrading facilities and equipment for AIDS research. Training The total number of full-time research training positions supported by NIH has been fairly constant since the late 1970s–between 11,000 and 12,000 a year–whereas the NIH research budget has increased from $3.6 billion to $7.6 billion. In terms of constant dollars, stipends have fallen. The proportion of the NIH budget going to training has declined accordingly, from 5.1 percent in 1980 to 3.8 percent in 1990. The 11,795 slots proposed for fiscal year 1990 were 308 less than the

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH number recommended by the NAS committee on national needs for biomedical and behavioral research personnel. Because research training is a long-term investment, it is not surprising that the NIH AIDS program has invested relatively little in training to this point. For fiscal year 1990, NIH allocated about $7.3 million (a little less than 1 percent of the AIDS budget) for 305 AIDS research training slots (2.6 percent of all NIH training slots). The administration is asking for the same number of slots in fiscal year 1991, with no increases in stipend levels or tuition. Recommendation 3.27: Support should be increased for pre- and postdoctoral training–to a level (about 3 percent of the budget) comparable to other training programs within NIH–in a wide range of AIDS-related disciplines: for example, molecular biology, virology, cell biology, immunology, epidemiology, behavioral sciences, infectious diseases, and clinical medicine. Increases should also be made in the number of predoctoral slots supported by NIGMS and the postdoctoral training grants supported by NIAID. Animal Models The lack of a single good animal model of HIV infection and disease progression is still a major impediment to research on AIDS pathogenesis, treatment, and prevention. NIH is currently underwriting development of several promising models including HIV in transgenic and severely immunodeficient mice, SIV in macaque monkeys, and HIV in chimpanzees. For example, as discussed earlier, the recent demonstration of experimental vaccination and protection from infection in the SIV-macaque model holds considerable promise for the development of an effective vaccine against HIV. An expanded effort to exploit the SIV model, however, requires better understanding of the immune system of rhesus monkeys and a larger supply of them for future vaccine research. NIH should also support the development of other animal models. Recommendation 3.28 NIH should develop a plan that addresses animal resource needs for future research, especially vaccine research. For example, the rhesus monkey population available for research should be increased to the level required to support the expanded program of studies on SIV. This should include not only an expanded breeding program but also a larger program of research on the biology of rhesus monkeys and the construction of additional biocontainment facilities. Facilities and Equipment AIDS research requires special facilities and equipment to ensure safe handling of HIV and HIV-infected specimens and to permit state-of-the-art research techniques. NIH has carried out some upgrading of research facilities and equipment through regular research grant mechanisms (e.g., center core grants, cooperative agreements), and in 1989 it funded a one-time competition for 50 facility improvement grants. Historically, NIH has played a major role in underwriting the construction of biomedical research facilities and instrumentation. During the years of the Health Research Facilities Act (1956–1968), the agency supported the construction of about 19 million square feet of health-related laboratory research space, 60 percent of all such space constructed in those expansion years. Some institutes (NCI, NHLBI, and NEI) also had small construction programs during the 1970s, but little construction was underwritten in the 1980s (only about $7 million a year). Many observers consider the overall current condition of biomedical research

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH facilities deplorable, with the majority of facilities in need of renovation, upgrading, and expansion. Yet in an era of tight funds, there has been no consensus on the appropriate federal role in restoring or expanding the physical infrastructure of biomedical research. Congress appropriated $28.9 million for AIDS facilities improvement and associated equipment in 1988 and 1989, enough for 50 small project grants, but it turned down an NIH request for $150 million in matching funds for construction in fiscal year 1988. No additional funds for facilities or equipment have been budgeted in 1990, and none have been requested for 1991. (Chapter 4 discusses intramural construction needs, for which NIH is requesting $88.6 million, including $16.5 million for AIDS-related construction projects.) Recommendation 3.29: The associate director of NIH for AIDS research should plan and oversee the implementation of a program for developing an adequate physical infrastructure for AIDS research. The actual administration of the program could be delegated to the National Center for Research Resources or to other NIH operational units. COMMUNICATION OF RESEARCH RESULTS An earlier part of this chapter discussed the issues surrounding the release of research results from clinical trials. However, the communication of research results applies to other areas besides clinical trials and encompasses several modes of information dissemination. This section examines NIH's efforts in this area. From the beginning of the AIDS epidemic, there has been an urgent need for swift communication of research activities and results among scientists, physicians, and other care providers; such information has also been sought by patients and the general public. In 1983 NIAID began a series of regional workshops to provide information on AIDS epidemiology, research, and patient management and on the ethical, legal, and psychosocial issues faced by health care workers who provide care to AIDS patients. In 1983 NIH also began publishing the AIDS Memorandum, a monthly report on AIDS research results that emphasized studies that would not otherwise be published (e.g., studies with negative results), as well as preliminary results of research that would appear later in peer-reviewed journals. In addition, since 1986 the OAR has compiled an in-house quarterly progress report on NIH intra-and extramural AIDS research. In the past several years, NIH has developed a more extensive public information program than had been in place previously. NIAID has taken the lead in information dissemination to patients, providers, and the general public about available drugs, clinical trials, and effective therapies. For example, it has continued the regional meetings and recently increased efforts to reach more minority health care workers with AIDS information. NIAID has also sponsored workshops and speakers at national meetings of minority health professions organizations. Other NIAID activities include the dissemination of a number of brochures about its treatment research program, contributions to the support of the AIDS/HIV Experimental Treatment Directory published by the American Foundation for AIDS Research, and arrangements for entering AIDS clinical trials into PDQ, NCI's on-line information base for physicians on treatments and clinical trials. In 1989 NIAID introduced the AIDS Clinical Trials Information Service in cooperation with CDC and the FDA. This service, which can be accessed by a toll-free telephone number or through the National Library of Medicine's (NLM) on-line information service, provides information in English and Spanish about NIH-sponsored clinical trials and experimental therapies for AIDS and AIDS-related diseases, and about drug company-sponsored trials known to the FDA. NIAID's Office of Communications also distributes Backgrounders and other materials with current information on

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH AIDS research results. Also in 1989 NIAID's Division of AIDS began a bimonthly publication, AIDS Research Exchange, to “provide timely information on major developments, issues, and events related to AIDS research sponsored or conducted by the NIAID.” NIAID has announced the results of some clinical trials as “clinical alerts ” mailed to every physician in the country (a mechanism that has been criticized as medicine by press release). In March 1990 NIAID held the first of a planned series of “state-of-the-art” consensus conferences to develop practice guidelines for the use of new therapies; the first conference resulted in recommendations for the use of AZT in treating patients with early HIV disease. Other NIH components besides NIAID are also involved in disseminating information on AIDS research. For example, NHLBI carries on information and education efforts because of its role in ensuring a safe blood supply for the nation. The institute established the National Blood Resource Education Program in 1987 to promote the adequacy and safety of the blood supply and its appropriate use, and has sponsored several consensus conferences on related issues. The NLM supports several AIDS-related information efforts. The Health Omnibus Program Extension of 1988 authorized NLM to create a “data bank on the results of research with respect to AIDS.” The library has also published a printed bibliography of AIDS citations since 1983. In 1988, the NLM added AIDSLINE, a bibliographic data base on AIDS basic research, epidemiology, diagnosis, treatment, control, prevention, and policy and administration, to MEDLARS, the NLM's family of on-line data bases. AIDSLINE contains more than 23,000 references to the published literature on AIDS dating from 1980 and is adding about 700 new citations a month. In late 1989, the NLM added two more data bases, AIDSDRUGS and AIDSTRIALS, which provide information on clinical trials of AIDS drugs and vaccines, including general patient inclusion and exclusion criteria. These data bases contain the same information available through NIAID's toll-free telephone service. The committee commends NIH's support of an extensive AIDS communications program for scientists, clinicians, patients, and the general public. Nevertheless, continuing research advances with implications for prevention, diagnosis, and treatment raise new and urgent questions about early dissemination that NIH must address. (A discussion of this issue was presented in the earlier section on clinical trials.) The committee encourages NIH to continue its present efforts and, in addition, to solicit input from the public and scientific community and periodically review its programs.

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH TABLE 3.1 Funding for HIV-related Epidemiological Research (in thousands of dollars), National Institutes of Health, Fiscal Year 1990 Institute Amount National Institute of Allergy and Infectious Diseases 71,500 National Heart, Lung, and Blood Institute 18,290 National Cancer Institute 16,663 National Institute of Child Health and Human Development 15,017 Fogarty International Center 2,938 National Institute of Dental Research 550 National Institute of Arthritis and Musculoskeletal and Skin Diseases 320 National Institute on Aging 274 National Center for Nursing Research 241 Total 125,793 SOURCE: Office of the Assistant Secretary for Health, Budget Office,U.S. Department of Health and Human Services.

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH TABLE 3.2 Status of National Institute of Allergy and Infectious Diseases (NIAID) Research on Opportunistic Infections   Basic Research FY89 Clinical Research FY89       In Vitro Tests   Organism Culture Screen Animal Models Division No. of Grants No. of Contracts Treatment Available No. of ACTG Trials No. of Other Trials NCDDG-OI Grants FY90 Other Involved Institutes Pneumocystis carinii No In dev. Yes DAIDS 9 4 Yes 12 10 Yes NHLBI, NIGMS   DMID 1 0     DAIT 1 0   Toxoplasma Yes Yes Yes DIADS 3 0 Yes 1 2 Yes NEI, NICHD   DMID 9 0   Cryptosporidium No No In dev. DAIDS 1 0 No 1 2 Yes NIDDK Isospora No No No DAIDS 0 0 Yes 0 0 No NIDDK Microsporidium No No No DAIDS 0 0 No 0 0 No   Candida Yes Yes Yes DAIDS 4 3 Yes 0 3 Yes NCI, NIDR, NHLBI   DMID 15 0   Cryptococcus Yes Yes Yes DAIDS 4 0 Yes 3 3 Yes     DMID 5 0   Histoplasma Yes Yes Yes DAIDS 1 0 Yes 1 0 No NEI   DMID 5 0   Coccidiodes Yes Yes Yes DAIDS 0 0 Yes 0 0 No     DMID 3 0   Mycobacterium avium Yes Yes Yes DAIDS 4 3 Yes 0 3 Yes     DMID 4 0   Mycobacterium Yes Yes Yes DAIDS 0 0 Yes 0 1 No NIA tuberculosis DMID 3 3   Salmonella Yes Yes Yes DAIDS 0 0 Yes 0 0 No NIDDK, NIEHS,   DMID 9 0   NIGMS Treponema pallidium No No Yes DAIDS 0 0 Yes 0 0 No     DMID 9 0   Cytomegalovirus Yes Yes Yes DAIDS 5 0 Yes 8 6 Yes NCI, NEI, NIGMS,   DMID 16 6   NHLBI, NICHD Herpes simplex Yes Yes Yes DAIDS 0 1 Yes 1 0 No NCI   DMID 31 1   Herpes zoster Yes No No DAIDS 0 0 Yes 0 1 No     DMID 8 7   NOTE: Abbreviations: ACTG, AIDS Clinical Trials Group; DAIDS, Division of Acquired Immunodeficiency Syndrome; DMID, Division of Microbiology and Infectious Diseases; DAIT, Division of Allergy, Immunology, and Transplantation; FY, fiscal year; NCDDG-OI, National Cooperative Drug Discovery Groups program for opportunistic infections; NHLBI, National Heart, Lung, and Blood Institute; NIA, National Institute on Aging; NIEHS, National Institute of Environmental Health Sciences; NIGMS, National Institute of General Medical Sciences; NEI, National Eye Institute; NICHD, National Institute of Child Health and Human Development; NIDDK, National Institute of Diabetes and Digestive Kidney Diseases; NCI, National Cancer Institute; NIDR, National Institute of Dental Research. SOURCE: National Institute of Allergy and Infectious Diseases, NationalInstitutes of Health.

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH TABLE 3.3 NIH Clinical Trials Spending (in thousands of dollars and as percentage) by Institute Institute 1988 Dollars Percent 1989 Dollars Percent 1990 Dollars Percent 1991 Dollarsa Percent NCI 14,778 17 23,487 20 35,373 22 37,809 21 NIDR 0 0 209 0 221 0 234 0 NIAID 64,864 76 84,609 74 118,325 72 133,230 72 NICHD 2,683 3 2,739 2 6,000 4 7,900 4 NEI 3,372 4 4,006 3 4,524 3 4,799 3 NIDDK 198 0 0 0 0 0 0 0 NCNR 247 0 0 0 0 0 0 0 Total 85,895 100 115,050 100 164,472 100 183,972 100 NOTE: Abbreviations: NCI, National Cancer Institute; NIDR, National Institute of Dental Research; NIAID, National Institute of Allergy and Infectious Diseases; NICHD, National Institute of Child Health and Human Development; NEI, National Eye Institute; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; NCNR, National Center for Nursing Research. aEstimated. SOURCE: Division of Financial Management, National Institutes ofHealth.

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THE AIDS RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH REFERENCES ADAMHA (Alcohol, Drug Abuse, and Mental Health Administration). 1990. Mission statement and functional statements. Rockville, Md. Photocopy. Bolognesi, D. P. 1989. Progress in vaccines against AIDS. Science 246:1233–1234. CDC (Centers for Disease Control). 1990a. Fact Book FY 1990. Atlanta, Ga.: CDC. CDC. 1990b. HIV-related behavioral science initiatives. Atlanta, Ga. Photocopy. Hellinger, F. J. 1990. Forecasting the number of AIDS cases: An analysis of two techniques . Inquiry 27:212–224. IOM/NAS (Institute of Medicine/National Academy of Sciences). 1988. Confronting AIDS: Update 1988. Washington, D.C.: National Academy Press. Larson, E. 1989. Testimony of the American Nurses' Association on NIH AIDS Research Programs. Testimony before the Committee to Study the National Institutes of Health AIDS Research Program, December 5. Laughon, B. E., H. S. Allaudeen, J. M. Becker, W. L. Current, J. Feinberg, J. K. Frenkel, R. Hafner, W. Hughes, C. A. Laughlin, J. D. Meyers, L. K. Schrager, and L. S. Young. In press. Summary of the workshop on future directions in discovery and development of therapeutic agents for opportunistic infections associated with AIDS. J. Infect. Dis. NCNR (National Center for Nursing Research). 1989. AIDS research and training program: 1989 awards. National Institutes of Health, Bethesda, Md. Photocopy. NCNR, Priority Expert Panel on HIV Infection. 1990. HIV Infection: Prevention and Care. NIH Pub. No. 90-2417. Bethesda, Md.: National Institutes of Health. NIAID (National Institute of Allergy and Infectious Diseases). 1990. Pathogenesis branch: Mission, goals and strategies. National Institutes of Health, Bethesda, Md. Photocopy. NIH (National Institutes of Health). 1987. NIH Organization and Functions. Washington, D.C.: U.S. Government Printing Office. Pharmaceutical Manufacturers Association. 1990. AIDS Medicines in Development: Drugs and Vaccines. Washington, D.C.: Pharmaceutical Manufacturers Association. Raub, W. F. 1988. Health and Behavior Research Initiatives by the National Institutes of Health, FY 1989. Bethesda, Md.: National Institutes of Health. Rolfs, R. T., and A. Nakashima. 1990. Epidemiology of primary and secondary syphilis in the United States, 1981 through 1989. J. Am. Med. Assoc. 264:1432–1437. Turner, C. 1990. The National Research Council, Committee on AIDS Research and the Behavioral, Social, and Statistical Sciences. Testimony before the National Commission on AIDS, May 7. Turner, C. F., Miller, H. G., and Moses, L. E., eds. 1989. AIDS, Sexual Behavior, and Intravenous Drug Use. Washington, D.C.: National Academy Press. U.S. Congress, Senate. 1989. Departments of Labor, Health and Human Services, and Education and Related Agencies Appropriation Bill, 1990. Report 101-127 to accompany H.R. 2990. 101st Cong., 1st sess., p. 166. Weislow, O. S., R. Kiser, D. L. Fine, J. Bader, R. H. Shoemaker, and M. R. Boyd. 1989. New soluble-Formazan assay for HIV-1 cytopathic effects: Application to high-flux screening of synthetic and natural products for AIDS-antiviral activity. J. Natl. Cancer Inst. 81:577–586.