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The AIDS Research Program of the National Institutes of Health (1991)

Chapter: 3 Elements of the NIH AIDS Research Program

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Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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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.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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  • 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

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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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

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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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.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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).

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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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.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
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

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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  • The MACS and SFMHS determined the risk of occurrence of opportunistic infections,4 and NCI-sponsored studies recently discovered an increase in non-Hodgkin 's lymphoma, among HIV-infected persons.

  • A study sponsored by NCI and NICHD demonstrated that mothers who did not transmit HIV to full-term babies had antibody reactivity to a specific epitope of gp120; the majority of mothers of babies who became infected lacked antibodies to gp120.

  • The MACS has studied surrogate markers of HIV disease, particularly those that might predict progression to AIDS by an asymptomatic person. Data generated by the MACS showed that CD4+ cell counts, neopterin levels, and soluble beta-2-microglobulin, taken as an aggregate, are more predictive of progression to AIDS than CD4+ cell counts alone.

  • Using polymerase chain reaction and viral culture techniques, NIAID investigators determined that HIV infection may be present for up to 42 months before seroconversion.

  • NIAID-sponsored epidemiological studies of the immunopathogenesis of HIV infection provided important information on antibody-dependent cellular cytotoxicity and the responses of natural killer cells, lymphokine-activated killer cells, and alpha interferon and their role in moderating the effects of HIV. Data on alterations in lymphocyte blastogenesis and gamma interferon production have also been gathered.

NIH's Role in Epidemiology Research

Within the PHS, HIV epidemiology studies are conducted by CDC and ADAMHA, as well as NIH.5 The research perspectives represented by these three agencies are fundamentally different, and they support varying proportions of epidemiological studies. ADAMHA funds only a small fraction of PHS initiatives in this area (less than 10 percent), focusing on the role of drug use as it relates to HIV infection; this leaves the vast majority of studies to be supported by CDC and NIH. NIH epidemiological research focuses on the underlying biological processes of HIV infection; in contrast, CDC studies focus predominantly on the identification of disease patterns in populations and the risk factors associated with HIV infection. In fiscal year 1990, CDC supported more than 87 percent of PHS HIV-related surveillance and NIH supported 8.2 percent. In contrast, NIH supported 66.3 percent of PHS efforts in population-based research (which includes natural history studies), compared with 21.6 percent supported by CDC. These figures reflect the traditional missions and capabilities of the two agencies. CDC has the capacity, through its Epidemiological Intelligence Service, to respond quickly and flexibly to emergencies, whereas NIH's strength is its capacity to conduct large, detailed, long-term studies. The two agencies also have different constituencies: CDC interacts primarily with state and local health departments, and NIH works with basic and clinical researchers.

Establishing Epidemiological Research Priorities

The committee believes that in the area of epidemiological research NIH should clearly identify those scientific questions that are most important to its mission of finding treatments and a vaccine for HIV infection. The natural history of HIV infection is changing dramatically as the virus affects populations other than homosexual men and the effects of treatment are taken into

4  

Currently, CDC-sponsored epidemiological studies record a person 's presenting condition and, where possible, cause of death. In contrast, NIH-sponsored epidemiological studies, as a result of extensive data gathering on clinical parameters and their prospective study design, allow an understanding of the sequence of occurrence of opportunistic infections.

5  

Although ADAMHA's and CDC's HIV epidemiology efforts have contributed significantly to an understanding of the epidemic, they are addressed in this report only in terms of their relation to NIH's HIV epidemiology efforts.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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account. For example, preliminary studies indicate that the types and patterns of opportunistic infections experienced by women and IV drug users are significantly different from those experienced by homosexual men. In addition, data characterizing the effects of treatments and prophylaxis are incomplete; research has not yet determined, for example, whether PCP prophylaxis extends life in HIV-infected persons. Data describing HIV incidence and prevalence are also incomplete, a critical gap for efforts to identify suitable populations for vaccine trials and promising avenues of investigation for therapeutics; these data are also essential for planning, developing, and assessing prevention programs. Continued epidemiological research is thus essential to an understanding of the emerging profile of HIV disease.

Given the many scientific questions yet to be answered, and the need to use available resources efficiently, the committee considers this an appropriate time for NIH to reassess its priorities for epidemiological research, including a review of ongoing research and careful planning for future epidemiological studies. As part of the priority-setting process, NIH should identify the key scientific questions that are most important to its mission. Moreover, this evaluation of the size and focus of the present program should involve outside advice, either through an ad hoc outside review group of epidemiological researchers selected by the NIH director (similar in nature to the committees established by NIAID to review the WITS and HATS studies) or by the epidemiology subcommittee of the APAC (described in Chapter 2). Over the longer term, the planning and evaluation of AIDS epidemiology efforts, including the epidemiology component of the five-year plan recommended in Chapter 2, could be overseen by the epidemiology subcommittee of APAC.

The committee is concerned that some epidemiological studies may be maintained to a point of diminishing scientific return compared with other studies that might be supported. There is an understandable reluctance to disband long-standing cohorts that are still producing information. However, given the emerging research opportunities and current fiscal constraints, NIH must carefully assess whether the data produced by long-running studies are still worth the investment. Epidemiological research should be routinely evaluated for continued relevance and adjusted to the changing course of the epidemic as, for example, more and more members of older cohorts progress to AIDS, members of younger cohorts become infected, and new risk groups are identified. NIH must also identify emerging research opportunities in the international arena and their potential value for future trials of therapeutics and vaccines.

Recommendation 3.7: NIH should reassess its epidemiological research priorities; evaluate ongoing research, discontinuing less productive or redundant studies and expanding studies in groups experiencing higher rates of HIV infection; and reassess the size of the total NIH epidemiology program in light of fiscal constraints and other emerging research needs. This reassessment should involve external advice.

Coordination of Studies

The committee believes that the types of epidemiological studies supported by the various PHS agencies provide different but equally important kinds of information that contribute to a full understanding of the epidemic. Epidemiological research is unique in that much of it depends on the maintenance of large cohorts of human subjects over an extended period of time, and the data serve to identify promising avenues of investigation for a number of research areas including vaccines, drug development, clinical trials, nursing, behavioral sciences, and epidemiology itself. Because of its unique character and indispensable role in providing direction for other programs, it is essential that studies be carefully planned and coordinated within NIH, with other PHS

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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agencies, and with outside agencies to reach consensus on the appropriate epidemiological research agenda and ensure that high-priority research questions are being addressed and that data are shared. At present, some mechanisms exist for identifying research needs and facilitating coordination; these include agreements between NIH institutes, clearance of proposed RFAs through the NIH Office of Extramural Programs, the FIC-sponsored International Network for AIDS Research and Training, informal discussions between researchers, and, until it was recently dissolved, the NAPO-sponsored Epidemiology and Surveillance Subcommittee of the PHS Executive Task Force on AIDS. These mechanisms have resulted in the collaborative studies previously noted in this section, but despite these successes, some unproductive overlap has also occurred. For example, out of a laudable desire to quickly establish cohorts to investigate perinatal transmission, several PHS agencies established cohorts that were too small to have sufficient statistical power to answer key research questions. Although interorganizational coordination is always difficult and requires constant effort and attention, NIH must continue to work to identify opportunities for collaboration between institutes and with other PHS agencies to ensure that gaps are identified or addressed, duplication is avoided, and cohorts are of sufficient size to enable meaningful statistical analysis. There should also be a coordinating mechanism at the PHS level to include NIH, CDC, and ADAMHA.

Recommendation 3.8: NIH should pursue collaborative efforts among its institutes and with other PHS agencies sponsoring epidemiological research to address all first-priority epidemiological issues, avoid duplication, and ensure adequate sample and cohort sizes.

BEHAVIORAL RESEARCH

The epidemic of HIV infection and AIDS is both a biological and a behavioral phenomenon, and efforts to contain its spread must look to both biomedical and behavioral sciences for interventions. Since the discovery of the virus and its modes of transmission, there have been significant advances in treatment for HIV disease. Historically, however, the discovery of effective chemotherapies and vaccines has not guaranteed success in controlling sexually transmitted diseases (STD) or other types of infection. For example, although penicillin has been an important and effective part of the campaign against syphilis for more than 40 years, this sexually transmitted disease persists and in fact today is on the rise (Rolfs and Nakashima, 1990). Outbreaks of childhood measles also still occur, despite the availability of a safe, effective vaccine. Disease prevention, then, often requires more than biomedical technologies. HIV infection is an example of an incurable but preventable disease that is amenable to behavioral intervention.

The committee believes NIH has neglected AIDS-related behavioral research, the results of which are inadequate funding and an underdeveloped knowledge base (compared with such disciplines as immunology and virology), absence of a behavioral research infrastructure (including a paucity of Ph.D.-level professionals), and lack of understanding of the behaviors central to the transmission of HIV. Lack of knowledge regarding patterns and determinants of sexual and drug-using behaviors in the general public, as well as in groups at particular risk for HIV infection, has hampered public health efforts to develop health education interventions for the prevention of AIDS. The committee considers increased attention and funding to be warranted, given the lack of scientific data on behaviors related to HIV infection, the seriousness of the HIV/AIDS epidemic, available research opportunities in the field, and the potential public health benefits such research could realize.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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In fiscal year 1989 the Office of the Assistant Secretary for Health (OASH) reported that NIH spending for behavioral research was $5.7 million. Of this amount, funding for human behavioral research was $4.6 million (0.76 percent of the total NIH research budget); the remaining $1.1 million went to the Animal Resources Program in the Division of Research Resources to support the use of chimpanzees in studying HIV infection. OASH estimates for behavioral research in fiscal years 1990 and 1991, respectively, are $3.4 million and $3.2 million, or 0.45 and 0.39 percent of the total NIH research budget. Thus, funding for human behavioral research has decreased since fiscal year 1989 both in total amount and as a percentage of the total NIH AIDS research budget.

Behavioral research spans a broad spectrum. It can include the use of epidemiological techniques to identify the distribution of behavioral risk factors, and basic research designed to understand the etiology, or underlying determinants, of behavior. Such research may include, for example, studies of the physiological, psychological, and social mediators that influence and modify behaviors relevant to the transmission of HIV. It also includes efforts to evaluate the effectiveness of interventions intended to modify behaviors. This may include design and assessment of strategies to prevent the initiation of high-risk behaviors, reduce recidivism, or test the efficacy of culturally specific behavioral strategies to reduce risk behaviors for HIV infection.

Significant research opportunities exist in the field of behavioral research. For example, very little is known about the prevalence of sexual behaviors, especially in minority groups, the adolescent population, women, the over-50 age group, and prostitutes (male and female); even less is known about their etiology. As an illustration of a significant data deficit, estimates of the number of men who engage in same-gender sex figure prominently in calculations of HIV prevalence; yet the figures used by the PHS in those calculations were derived from Kinsey's studies on male sexual behavior from the period 1938–1948 (Turner, 1990). The precision of two methods currently used to forecast the AIDS epidemic, trend analysis and back calculation, is also hampered by a lack of information about the basic determinants of HIV incidence; for example, little information is available about the average number of sexual contacts within certain population groups and the probability that these contacts are made with uninfected individuals (Hellinger, 1990). Data are scarce on initiation into early sexual activities and the influence of family and peer groups on sexual behavior and contraceptive use (CDC, 1990b). It is also unclear how much of the sexual activity of adolescence is motivated by sexual desire and how much results from the desire for peer acceptance and other nonsexual motives (Turner et al., 1989).

Significant gaps also exist in understanding intervention strategies. It is known that, for behavior to change, individuals must recognize a problem, be motivated to act, and have the knowledge and skills necessary to perform the action. However, data on how best to present information, instill and maintain motivation, and inform individuals remain incomplete. For example, studies have shown that information is necessary but often insufficient by itself to effect behavioral change; the association between knowledge and attitudes on one hand, and behavior on the other, however, remains unclear (Turner et al., 1989). The effectiveness of fear as a motivating element in AIDS prevention messages also is not well understood; nevertheless, PHS-sponsored information and prevention and treatment programs for sexually transmitted diseases often employ fear-evoking messages. Research has shown that, to be effective, information must be delivered in a manner that is comprehensible, convincing, and relevant to the audience it is intended to reach. Achieving this goal will require a much greater understanding of the perspectives and culture of the various ethnic, racial, social, age, and sexual orientation groups that currently make up the national population (Turner et al., 1989). Also necessary is a better understanding of the effects of different intervention strategies among different populations. For example, although some strategies have been effective in certain populations (i.e., gay men), it is not known whether the

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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same approaches would successfully solicit cooperation and motivate change in other populations such as adolescents, minorities, women, or prostitutes.

The public health consequences of continued neglect and inadequate funding of behavioral research could be severe. Effective interventions require an understanding of the behaviors that place a person at risk for acquiring HIV/AIDS, especially in view of the fact that modification of risky behavior is the only currently available way to prevent HIV infection. Getting ahead of the epidemic requires foresight to limit the spread of infection in populations and regions that currently have a low prevalence of AIDS and HIV infection; such opportunities should not be overlooked, for, once lost, they cannot be recaptured. Adolescents are generally recognized as a population for which prevention activities could have a great impact. The large and growing middle-aged and older segments of the population also deserve attention to forestall any possibility that the epidemic may become established in the more than 60 million people aged 50 and older. Currently, women of childbearing age still have a low HIV prevalence rate overall and also represent an excellent opportunity to avert the spread of HIV infection. Yet before intervention strategies can be designed to prevent the spread of HIV to those who are not yet infected, it is essential to know which behaviors to target, in whom they occur, and how they can be modified.

Given the lack of understanding of behaviors related to HIV infection and of ways to change them, the committee believes that there is a role for ADAMHA, CDC, and NIH in supporting behavioral research. All three agencies currently conduct behavioral research, but the type and focus vary significantly according to each agency's respective mission. ADAMHA's mission is to find scientifically based solutions to alcohol, drug, and mental health problems and to promote effective strategies to deal with the health problems associated with the abuse of alcohol and drugs and mental illness (ADAMHA, 1990). The agency sponsors research that principally addresses the neuropsychological changes encountered after HIV infection occurs and the etiology and role of drug abuse (including alcohol) in HIV infection. The ADAMHA HIV/AIDS program has a unique focus in that the agency combines research on the biological, behavioral, and psychological aspects of HIV infection with intervention research and the provision of clinical services. In contrast, CDCs mission is to prevent unnecessary disease, disability, and premature death, and to promote healthy lifestyles (CDC, 1990a). To this end CDC supports mainly applied behavioral research that is directly related to the implementation and assessment of broad-scale education and prevention programs. NIH's mission is to conduct and support research on the causes, diagnosis, prevention, and cure of diseases in humans (NIH, 1987). In keeping with this mission, NIH supports a small amount of basic behavioral research on the determinants of HIV-related behaviors based on the institutes' specialized constituencies and research interests. For example, investigators at NICHD are studying developmental components of sexual behavior, whereas NIAID researchers are incorporating interventional behavioral research into clinical research on sexually transmitted diseases. Thus, ADAMHA supports basic and applied research; CDC focuses on programs of disease surveillance and control, with mainly applied research examining behavioral change interventions (particularly in high-risk groups) as part of specific efforts in disease prevention and health promotion; and NIH supports mostly basic research, whose findings provide the basis for the design of actual interventions by CDC and other public health agencies.

As the government's principal biomedical research organization, NIH sponsors behavioral research in areas other than AIDS in which the disease burden to society is significant, such as cancer and heart disease. For example, NCI's Cancer Prevention and Control Program supports behavioral research on a range of topics from nutrition to smoking cessation. In fiscal year 1990, NCI spent 5 percent of its budget on behavioral research. NHLBI also devotes substantial funding to behavioral research and interventions in areas such as hypertension and cardiovascular disease; the institute spent approximately 3.3 percent of its budget on behavioral research. Overall, NIH

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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devotes approximately 3.1 percent of its funding to behavioral research (Raub, 1988). The comparable figure for AIDS behavioral research was 0.45 percent. (This is not to say that the proportion of NIH resources devoted to behavioral research has been optimal; indeed, the Senate Committee on Appropriations directed NIH to establish a comprehensive 10-year plan for steadily increasing its funding of health and behavioral research [U.S. Congress, Senate, 1989].)

CDC has been making a large investment in applied behavioral sciences research with regard to AIDS. This fact, however, does not relieve NIH of its responsibility to support and conduct such research; indeed, other committees (e.g., Turner et al., 1989) have noted particularly pressing needs for behavioral research on AIDS and strongly recommended an NIH role. This committee believes that, similar to its work in heart disease and tobacco use, NIH can play a key role in supporting basic research to understand the etiology of sexual and drug-using behaviors and in initiating demonstration projects to evaluate intervention strategies. This research may also benefit efforts to prevent transmission of other sexually transmitted diseases and the initiation and continuation of illicit drug use. The committee commends present NIH efforts (i.e., NIAID's efforts to integrate behavioral research with biomedical research through its Sexually Transmitted Diseases Cooperative Research Centers and NICHD's research on adolescents) but considers more research to be needed.

Recommendation 3.9: The NIH AIDS program should increase its support for behavioral research, especially for basic behavioral research (e.g., research designed to understand the etiology or underlying causes of behaviors and evaluate the effectiveness of interventions to modify particular health-related behaviors) on behaviors relevant to the transmission of HIV, including but not limited to human sexual development and practices and (in coordination with ADAMHA) drug addiction and abuse.

As behavioral research becomes a greater part of the NIH and PHS research portfolio, it will require careful planning and coordination to develop appropriate research agendas and clearly define agency roles. At present PHS has mechanisms in place to designate responsibility for research areas and prevent unproductive duplication; these include agreements between NIH institutes, clearance of proposed RFAs through the NIH Office of Extramural Programs, posting of proposed RFAs on a computerized bulletin board for review by other NIH and ADAMHA components, and informal discussion among researchers. These mechanisms, however, do not provide for early-stage coordination and lack high-level PHS oversight. At one point, the PHS Executive Task Force on AIDS had several subcommittees focusing on specific components of behavioral research (e.g., addiction and behavior), but these committees have been disbanded in preparation for a reshaping of all task force committee structures. This committee believes that the PHS should sponsor conferences, involving appropriate NIH, CDC, and ADAMHA officials and behavioral scientists, to identify promising areas of behavioral research, develop a PHS behavioral research agenda, and make recommendations on methods to improve coordination among PHS agencies sponsoring behavioral research.

As noted earlier in this section, the AIDS epidemic has highlighted the need for current data that are representative of the general population to guide the design of behavioral interventions on sexual behavior. To fill this data gap, NICHD proposed a national survey of health behaviors and AIDS risk prevalence that included questions on sexual relationships, partner characteristics, sexual behaviors with partners, and behaviors such as drug use that put people at risk for AIDS. The survey was also intended to provide a research basis for designing, implementing, and evaluating education and intervention programs to stop the spread of HIV. Despite the value of such information, however, the survey has not as yet been performed. NICHD sought to conduct

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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a pretest to refine the questionnaire and identify possible design problems and sent the pretest survey questionnaire to OMB in December 1988. Since then it has undergone multiple reviews by OMB, the NIH Director's Office, the Office of the Secretary of Health and Human Services, and OASH, which has been holding the revised pretest since July 1989. Currently, negotiations continue regarding the content and design of the questionnaire, and the future of the full survey is uncertain. The committee believes that these protracted delays have had an injurious effect on the scientific process and on the progress of behavioral research on sexual behavior. The committee believes that the National Survey of Health and AIDS Risk Prevalence will provide invaluable information for efforts to prevent the spread of AIDS and HIV infection and should go forward as soon as possible.

Recommendation 3.10: The pretest questionnaire for the National Institute of Child Health and Human Development's National Survey of Health and AIDS Risk Prevalence should be finalized and released, and the study should be allowed to proceed immediately.

NURSING RESEARCH

High-quality nursing care of persons with AIDS, in conjunction with advances in medical therapy, is an essential component of ensuring a reasonable quality of life for persons who are living with HIV infection. Owing in part to improvements in treatment, the number of persons alive with AIDS continues to grow. CDC estimates that by 1993 between 151,000 and 225,000 persons will be alive with AIDS, compared with 48,000 in 1988, more than a threefold increase in five years (see Figure 1.1). NIH's stated goal is to convert HIV infection into a chronic, manageable illness, a shift in emphasis that will also require a concomitant shift in research foci. Currently, NIH supports a relatively small amount of research (less than 0.2 percent of AIDS research and training funds) on the chronic aspects of HIV infection: research addressing the care needs of HIV-infected persons amounted to only $730,150 in fiscal year 1989, and funds for training of professionals in this area totaled $119,504 (NCNR, 1989).

The purpose of nursing research is to effect both short- and long-term improvements in nursing practice, in addition to restoring patient health and speeding recovery from illness (Larson, 1989). Nursing research addresses a wide range of topics including relief of distressing symptoms resulting from the disease process, development of interventions to alleviate physical symptoms that are secondary to or incompletely relieved by medical intervention, identification of optimal ways to administer medical treatment, achievement of increased compliance with therapeutic regimens, management of therapeutic side effects, prolongation of distress-free intervals, and improvement of quality of life. The neglect and inadequate funding of nursing research have resulted in an underdeveloped knowledge base that must be improved if adequate care is to be provided to the thousands of HIV-infected persons who will be flooding the health care system by the mid-1990s. A report of the NCNR Priority Expert Panel on HIV Infection (1990) identified significant gaps in knowledge about the care of HIV-infected persons:

  • care needs across the spectrum of HIV infection;

  • development and testing of nursing interventions to alleviate or control symptoms associated with AIDS or its treatment:

    • skin breakdown

    • nausea, vomiting, inadequate nutrition, loss of appetite, and diarrhea

    • psychological, neurological, physiological, and behavioral effects associated with organic brain changes, treatment, or being chronically ill

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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  • dementias and depression associated with AIDS in various health care settings

  • fatigue, weakness, pain, and sleep disturbances

  • dyspnea and respiratory complications;

  • the use of resuscitation and life support in AIDS care–patient outcomes and preferences;

  • the special care needs of elderly persons with AIDS, who often have substantial comorbidity and therefore present a difficult treatment and care challenge;

  • determination and evaluation of strategies to increase the compliance of HIV-infected persons with various treatment regimens;

  • therapeutic effects and cost-effectiveness of nursing interventions in different settings

    • comparison of patient outcomes and costs for dedicated hospital AIDS units compared with nursing care on general medical wards

    • factors affecting the incidence of cross-infection and nosocomial infections among AIDS patients in institutional settings

    • reorganization of hospice care to accommodate the AIDS patient's unique combination of aggressive drug therapies for opportunistic infections and palliative care and symptom control; and

  • nursing interventions to enhance or maintain the functioning of people with AIDS through their own self-care or by the development of effective strategies to assist and support informal caregivers (family, friends, volunteers).

In addition to studying the physiological and psychological aspects of nursing care and its delivery, nurses can also play an important role in evaluating the effectiveness of preventive interventions. Because health education and counseling are often the responsibility of nurses, and because nurses often occupy a central position within a multidisciplinary research team, they are uniquely placed to study the effectiveness of behavioral interventions. Such studies could include testing of models of risk identification and risk reduction in primary care settings. Currently, however, this type of nursing research is not being conducted, a situation that is unlikely to change without NIH support.

Recommendation 3.11: Support should be substantially increased for nursing research on the care of people with HIV-related illness.

PRECLINICAL DRUG DISCOVERY AND DEVELOPMENT

In the past 10 years NIH's drug development program has played a pivotal role in developing therapeutic agents for HIV infection. Now, like all of NIH's AIDS research programs, it faces a new era. The early years of the program saw little pharmaceutical industry involvement; consequently, many drug discovery efforts (e.g., the mass screening program for anti-HIV compounds) were supported almost exclusively by NIH. Since the success of AZT, however, pharmaceutical companies have been more willing to expand their internally funded development programs for agents targeting HIV and its related opportunistic infections. A range of new drugs including antivirals, cytokines, immunomodulators, and anti-infectives are now under development by pharmaceutical companies (Pharmaceutical Manufacturers Association, 1990). Given present research needs and the willingness of the pharmaceutical industry to develop certain types of therapeutics, the committee believes this to be an appropriate time to assess NIH's role in preclinical drug development.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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Preclinical drug development is part of a continuum of research that runs from basic science knowledge to clinical trials.3 Drug discovery and development efforts are applied to and focus on a specific outcome: creation of a new therapeutic. The process is subject to controls and regulation by the FDA, which requires the completion of critical path components,4 conducted under good laboratory practice (GLP)5 conditions, for all agents for which a sponsor of a human trial submits an IND application. To fulfill these requirements, a drug sponsor must be able to synthesize the drug for preclinical or clinical studies, assess its quality (purity) and detect it in biological fluids, and prepare the compound in pharmaceutical dosage forms suitable for administration to animals or humans.

At present, NIH supports preclinical drug development for anti-HIV agents within NCI, NIAID, and NIGMS. Funding for preclinical drug development in these three institutes totaled approximately $98 million for fiscal year 1990.

National Cancer Institute

NCI supports two major initiatives for preclinical discovery and development of anti-HIV drugs: a high-capacity screen to assess compounds for activity against the HIV virus and a program for the preclinical and early clinical development of drugs with anti-HIV activity. (Clinical drug development efforts are discussed in the next section on clinical trials.) NCI's fiscal year 1990 budget for the development of therapeutic agents was approximately $40 million.

The institute's rapid, high-capacity drug screen for anti-HIV activity is a unique resource. The assay procedure identifies agents active against HIV by detecting drug-induced suppression of viral cytopathic effects in T-4 lymphocytes (Weislow et al., 1989). The screen has a capacity of approximately 900 tests per week; since its implementation in 1987, more than 27,000 screening tests have been performed. To date, more than 7,000 unique chemical structures have been tested, and about 70, or 1 percent, have been identified as having anti-HIV activity.

Compounds for testing may be submitted to NCI from virtually any source, providing relevant structural and biological information accompany the submission. When a compound is submitted, the Acquisitions/Input Committee (composed predominantly of senior staff from the Division of Cancer Treatment [DCT]) reviews the current acquisitions inventory to decide whether to accept the compound for screening. If the compound is accepted, it is rated for priority and enters the screening program. All compounds progress through the NCI program in the same general manner. If a compound is shown to have in vitro anti-HIV activity, the Decision Network Committee (DNC) decides whether to proceed with further preclinical and clinical development. (The 20-member DNC includes senior NCI staff and representatives from NIAID.) If the DNC decides the compound should be considered for preliminary pharmacological and toxicological studies, it is followed by an operating committee, also composed of senior DCT staff, that monitors the preclinical testing. This system allows NCI to bring three or four promising anti-HIV drugs

3  

As used in this discussion, drug discovery and development encompass the acquisition and testing of materials, chemical synthesis and bulk drug production, toxicology and pharmacology studies, and formulation and production of a drug for use in a clinical trial.

4  

For anti-HIV drugs, critical path components include pharmacokinetics and toxicology studies, as well as synthesis and formulation of the compound. Agents for opportunistic infections require these four steps and animal-model efficacy studies.

5  

GLP guidelines are specified by the FDA and usually require special resources. For example, a laboratory operating under GLP conditions has a designated balance for weighing a specific compound and designated notebooks for recording all measurements made on the balance. In addition, these studies often require specialized containment facilities and specially trained staff; as a result they are often quite expensive.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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per year from preclinical to early clinical development. At the time of this report, twelve compounds identified through the screen were in the preliminary development stage and one was in late-stage development; however, no compound identified by the screen had as yet reached the clinical trial stage.

National Institute of Allergy and Infectious Diseases

NIAID supports preclinical drug discovery and development initiatives for HIV and opportunistic infections in three general areas: (1) targeted drug development, (2) basic and applied research, and (3) preclinical investigational new drug studies. In fiscal year 1990, NIAID's budget for the development of therapeutic agents was $44 million.

NIAID's major vehicles for targeted preclinical drug development are the National Cooperative Drug Discovery Group Program for the treatment of AIDS (NCDDG-HIV) and the National Cooperative Drug Discovery Group Program for the treatment of opportunistic infections (NCDDG-OI). Launched in fiscal years 1986 and 1990, respectively, the NCDDG programs account for more than half of NIAID's preclinical drug development budget (approximately $23 million). Both NCDDG programs are investigator-initiated efforts designed to foster collaboration among academic, private, and government laboratories on basic and applied research problems in the design and development of new therapies for the treatment of HIV and related infections. The programs use a rational approach to drug design; that is, researchers study an infectious organism 's structure and mechanism of replication and use this information to design therapies that target vulnerable features of the organism. If a promising compound is discovered by one of these groups, it can then be developed either by the private-sector participant or by NIH itself.

NIAID also supports about $20 million in investigator-initiated research related to drug discovery and development. Discovery grants are awarded to study the structure of proteins and viral enzymes; development grants concentrate on developing analogs and improving the formulation of therapies. As the third major part of its preclinical program, the institute maintains contracts to perform scale-up synthesis, assess drug purity, and develop dosage forms. In addition, it recently issued RFPs to expand its basic drug development capabilities for pharmacokinetic, bioavailability, and toxicology studies.

NCI and NIAID thus take different approaches and use their resources differently in the pre-clinical development of agents. NCI offers its resources in a programmatic manner; rather than a sponsor being able to utilize discrete NCI components, an agent enters NCI's system. In contrast, NIAID provides access to individual preclinical drug development resources, such as formulation, scale-up, and animal-model studies. NCI has a contract-based, large-scale mass screening program as opposed to the variety of biochemical and cell-based screens that can be made available to NIAID by NCDDG investigators. Moreover, under the terms of a 1989 interagency agreement between NCI and NIAID, 6 NIAID has sole responsibility for the acquisition and development of drugs for opportunistic infections and supports basic and applied drug development research on opportunistic infections throughout its divisions.

6  

The interagency agreement was signed March 7, 1989, by the directors of NCI and NIAID and the director of NIH. It is the third in a series of such agreements that outline the responsibilities and rights of the two institutes concerning AIDS-related research.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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National Institute of General Medical Sciences

NIH's Targeted Antiviral Program, launched in fiscal year 1987, funds research on molecular structure determination and analysis for the purpose of developing antiviral drugs for AIDS treatment. Initially, the program was funded by the NIH OD and managed by NIGMS. It is now funded and managed by NIGMS alone.

The Targeted Antiviral Program operates under the premise that the best way to design drugs is to delineate the detailed molecular dimensions and structure of a potential receptor site and then synthesize a specific molecule to fit that site. The program sponsors research in the areas of structural biology, x-ray crystallography, theoretical chemistry, and nuclear magnetic resonance imaging to develop new leads on agents that can be used in the treatment of AIDS and new methods for drug screening. Many of these projects require highly purified HIV proteins that are not readily available commercially. To meet this need, NIGMS recently established a Protein Expression Lab to produce HIV proteins of sufficient purity and in adequate quantities for structural studies.

NIH's Role in Preclinical Drug Development
Anti-HIV Agents

At present, preclinical drug development of anti-HIV agents is supported in a number of arenas. Within the industry, both large, established pharmaceutical houses and emerging biotechnology firms have shown interest in developing anti-HIV drugs. NIH intramural researchers have made significant contributions to understanding the mechanisms of action of compounds; extramural researchers have also shown interest in developing anti-HIV therapeutics. NIAID's NCDDGs actively pursue targeted drug development using a wide range of approaches.

The different groups that have demonstrated an interest in developing anti-HIV drugs possess varying levels of resources and thus require different levels of assistance to support the critical path studies necessary for submission of an IND application. Established pharmaceutical firms require the least amount of assistance as they generally have in-house capabilities for completing FDA-required critical path studies; many of these firms also have a long record of expeditious drug development and approval. Similarly, NCDDGs, which include an industry representative as part of the consortium, also have access to preclinical development resources. NCI intramural researchers have access to such resources through that institute's comprehensive drug development program. The greatest need for assistance is among small biotechnology companies and independent drug sponsors, which may have the resources to complete some but not all of the studies required in support of an IND application. (For example, some sponsors may not have the resources or facilities to conduct the necessary drug formulation or animal-model studies.)

It is unfeasible for NIH to act as a national nonprofit pharmaceutical firm and develop all possible candidate agents. To achieve the goal of making HIV infection a manageable, curable disease, the committee believes NIH should promote a wide range of approaches and offer selective support to a variety of sponsors. In particular, NIH should use its resources to assist sponsors of promising compounds that do not possess the resources to complete all the studies required for an IND application. The committee notes that NIAID has expressed interest in providing resources in this manner and encourages this approach. However, the private sector alone will never pursue all of the areas of drug development needed to address AIDS concerns because commercial firms generally develop only those drugs on which they can expect to make a profit. Consequently, NIH

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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should be prepared to develop promising compounds that would not otherwise be developed by the pharmaceutical industry.

Recommendation 3.12: The optimal role for NIH's preclinical drug development program should be to facilitate drug development by all sectors–governmental, academic, and private–and to develop drugs whose development is not likely to be supported by the pharmaceutical industry.

Regimens that use combinations of drugs with different mechanisms of action (i.e., that target multiple elements of the HIV life cycle) are a promising therapeutic approach. To establish such regimens it will be necessary to develop a variety of biochemical and cell-based screens that identify compounds active against the various HIV life-cycle stages. NCI's mass screen for anti-HIV agents does not identify drugs that work by all mechanisms of action. NIAID, which also has responsibility for identifying and developing anti-HIV compounds, does not have adequate resources to develop and use screening tests; instead, it relies on NCDDG investigators to perform testing on a voluntary basis. This arrangement causes delays in screening potential compounds and limits NIAID's ability to assess promising agents quickly and fully. Such testing will be vital in the development of combination regimens and is unlikely to be supported by industry. As a complement to NCI 's mass screening program, NIAID should have additional in-house resources to develop and use a broader range of screening tests for anti-HIV agents.

Recommendation 3.13: NIH should develop and support a range of screening tests for anti-HIV drugs. In addition, NIAID and its Division of AIDS should establish contract-based screening capabilities, and NIH should expand its intramural or dedicated extramural resources for mechanism-of-action studies for anti-HIV agents.

Agents for Opportunistic Infections

Within NIH, NIAID has sole responsibility for the acquisition and development of drugs for opportunistic infections (OI), and its divisions support basic and applied research in this area (Table 3.2). Research on opportunistic infections has a profile different from research on HIV for two reasons. First, although OIs are often referred to as one phenomenon, they are more precisely a collection of pathogens responsible for a host of protozoal, fungal, bacterial, and viral infections seen among AIDS patients. Second, the duration of support for basic research on the various organisms has varied widely, resulting in disparate levels of basic knowledge and varying availability of in vitro tests and animal models.

NIAID officials and researchers in the field have stated that one of the largest impediments in the development of drugs for opportunistic infections is inadequate basic knowledge about some of the organisms. For example, consider the following:

  • Pneumocystis carinii pneumonia–there is still debate as to whether the pathogen is a protozoa or a fungus; moreover, it cannot be cultured in vitro. (Between 60 and 80 percent of persons with AIDS contract PCP with an approximate 25 percent mortality rate.)

  • Cryptosporidium–knowledge about this organism is also limited. The pathophysiologic mechanism by which Cryptosporidium causes diarrheal disease is unknown, and the lack of suitable in vitro and in vivo model systems has hindered research.

  • Toxoplasmosis–present therapies cannot predictably eliminate the latent form of the parasite, which means that AIDS patients must continue lifelong suppressive therapy. There is also no diagnostic test available to discriminate between active and latent infection.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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  • Mycobacterium avium–very little is known about its biochemical pathways and the enzymes critical to its functioning.

In addition to a dearth of basic knowledge on many organisms, other impediments exist. Two obstacles to the rapid development of drugs for opportunistic infections are the lack of good animal models and in vitro tests (see Table 3.2) The availability of isolates for certain organisms has also been cited by researchers as an impediment to further research. As of the fall of 1990, NIAID/DAIDS had drug evaluation contracts for agents active against Pneumocystis carinii, Mycobacterium avium complex, and Candida albicans; it has expressed interest in expanding this capacity to include Toxoplasma gondii, Cryptococcus neoformans, Histoplasma capsulatum, and Cryptosporidium parvum. The committee encourages NIAID in these efforts to develop an increased screening capacity. Another obstacle involves the peer-review process, which some NIH officials and researchers have asserted impedes the expansion of research on opportunistic infections. Proposals to study organisms that have a more immature knowledge base have often had difficulty competing with more sophisticated proposals for research on organisms that are better understood. (There appears to be a perception among some researchers that prestigious investigators avoid this type of research and that it is less “glamorous” than working with HIV.) The committee believes that study sections reviewing applications for specific organisms should include individuals who are knowledgeable about the current state of the science for that organism. A final barrier cited by NIH officials has been the lack of a preclinical drug development capacity for OI agents. The committee notes that the NIAID advisory council recently approved proposals that would provide NIAID with the capacity to conduct pharmacokinetic, bioavailability, and toxicology studies, and it strongly endorses these efforts.

As noted earlier in this section, NIAID has expanded its OI research efforts by establishing six national cooperative drug discovery groups. NIH has contributed to the total research effort by sponsoring a workshop to identify research needs in this field. The committee commends NIH for both of these activities but is compelled to note that areas of further scientific opportunity still exist. Support by the pharmaceutical industry for basic research and animal-model studies related to opportunistic infections is unlikely. NIH should have the capacity to conduct this research and, indeed, all critical path studies required by the FDA for submission of an IND application for drugs for opportunistic infections.

Recommendation 3.14: NIH should increase its support for basic and applied research in the area of opportunistic infections. NIH should also facilitate the development of promising drugs for opportunistic infections through all the steps necessary to secure the IND application.

CLINICAL TRIALS

A major goal of the AIDS research program is the development for clinical use of treatments for HIV infection and the diseases it causes. To this end, clinical trials of therapeutic agents for AIDS and HIV infection are conducted by several institutes at NIH. These include NIAID, which has major extramural, intramural, and community-based systems; NCI, which conducts primarily intramural phase 1 studies; NICHD, which administers a network of extramural pediatric clinical trials centers; and the National Eye Institute (NEI), which has written several protocols and is currently running an extramural trial on ocular complications of AIDS. Table 3.3 shows funding for NIH AIDS clinical trials by institute for 1988 –1991.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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Once the federal government recognized the urgent nature of the AIDS epidemic, and the enormous challenge the disease presented, it began to increase substantially its support of AIDS-related research, the NIH therapeutics programs, and especially the NIAID clinical trials program. NIH was charged with developing the organization for a new, comprehensive drug evaluation program at the same time it was enrolling thousands of patients in clinical trials. Despite these formidable tasks, the short history of the NIH clinical trials program records several notable accomplishments, including

  • determination of the efficacy of AZT in the treatment of children with AIDS;

  • establishment of a national clinical trials network capable of testing new anti-HIV and anti-OI therapeutic agents;

  • recruitment of many talented investigators into AIDS clinical research;

  • extension of the use of AZT for persons with early and asymptomatic infections and a better understanding of the drug's most effective and safe dosage ranges; and

  • initiation of dozens of important clinical trials that promise to provide essential scientific information about treatment with a wide array of antiviral and anti-OI drugs.

The committee strongly believes that the rapid growth of the NIH clinical trials program and its undertaking of a much larger number of trials than were originally envisioned, involving thousands of patients, necessitate a reevaluation of the NIH clinical trials system to ensure that it functions both efficiently and cost-effectively; this section thus discusses the committee's findings and its recommendations for improving the performance of AIDS clinical research. The committee concentrated on the AIDS Clinical Trials Group program of NIAID' s Division of AIDS because it is NIH's largest AIDS clinical trials program and often provides the sites for clinical studies sponsored by other institutes. This section 's principal topics are (1) establishing a specific mission for the ACTG; (2) improving management and interinstitute coordination; (3) evaluating current systems to address areas of inefficiency; and (4) providing the staffing and funding necessary to perform the tasks assigned to the NIAID clinical research program. (As the report neared completion, NIH officials announced their intention to institute a number of measures that are similar to recommendations offered by the committee.7 The committee supports those plans and hopes that its recommendations will underscore the critical need for their implementation.)

Mission of the AIDS Clinical Trials Group

One of the major questions confronting NIH's AIDS clinical research program is how it defines the mission of the ACTG. Many of the NIH officials interviewed by the committee said that lack of a clear mission was the cause of many of the ACTG 's current problems, in that the ACTG undertook more trials than its staff and clinical resources could handle. The absence of a

7  

NIAID announced a number of changes in its clinical trials program at the September 1990 meeting of the NIAID advisory council. They included: (1) recompetition of all adult ACTUs in fiscal year 1992, with future funding levels tied to performance measures (e.g., overall accrual, timely submission of data, accrual of underrepresented populations); (2) special funding incentives for ACTUs that accrue more patients than the numbers specified by the ACTG; (3) establishment of a small contract program for rapid pilot and phase 1 studies of new agents, innovative studies of new therapies, and quick evaluations of unproven therapies, to be conducted by non-ACTU institutions; (4) a separate grant program for supporting applied clinical research at ACTUs in virology, immunology, and pharmacology (e.g., studies of drug resistance, surrogate markers of disease progression); and (5) regionalization of pharmacology and virology laboratory services to ACTUs. NIAID expects to carry out these changes within the current ACTG budget (adjusted for inflation). The council also approved a $15 million-a-year expansion of the pediatric ACTG to include more sites and to provide outreach, perinatal, and obstetrical services.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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clearly focused mission also contributed to unrealistic public expectations of the ACTG that led to severe criticism when those expectations were not satisfied. NIH must define the ACTG's mission more clearly with a focused statement of its scientific goals. Such a statement would delineate NIH's specific responsibilities and provide accountability for its AIDS clinical research program. In addition, it would clarify the division of responsibility between NIH and the pharmaceutical industry for clinical trials and between NIH and other government agencies for the provision of health care (see Chapter 1).

In terms of scientific goals, the ACTG leadership has sought to operate the trials group as a national nonprofit pharmaceutical company responsible for testing and obtaining approval for every potential AIDS drug at every trial phase. Thus, by June 1990, the ACTG network of 47 clinical centers was sponsoring nearly 90 active clinical trials and planned to start 33 more protocols before the end of 1990. This heavy workload stems in large part from strong societal and congressional pressure on NIH to provide new AIDS drugs rapidly. However, given the ACTG's currently limited resources (e.g., at the time of this report, the ACTG had only four medical officers who were responsible for advising its field investigators and managing all of the trials), the committee concludes that the ACTG cannot continue to perform high-quality work with the large number of trials now in progress and in planning stages.

Recommendation 3.15: The ACTG should focus its mission more narrowly and tailor the number of trials it conducts to that new mission, to currently available staff, and to the capacities of local AIDS clinical trial units.

In redefining the ACTG's primary mission, NIH must distinguish the tasks to which it is best suited and the tasks that are better left to the pharmaceutical industry, the other major resource for AIDS clinical trials in this country. Many of the major pharmaceutical firms have a long record of expeditious drug development and approval, and such firms will conduct many clinical trials. The committee recognizes, however, that pharmaceutical firms do not always perform trials well and that some small companies have little experience in conducting clinical research. In addition, pharmaceutical companies generally develop only those drugs on which they expect to make a profit, and the trials they conduct of those drugs are designed-to provide only those data that are necessary for marketing approval. The ACTG, on the other hand, as a multicenter, publicly funded system, is uniquely qualified to conduct clinical efficacy trials that are in the interest of the public's health but that are not usually done by major drug companies. Such studies, which often collect other useful data besides those required for approval, include drugs for small patient populations with particular opportunistic infections or AIDS-related cancers, testing of drugs in combination, “head-to-head” trials of drugs from different companies, and, rarely, postapproval (phase 4) trials that might change the indication for already approved drugs. The large size and multicenter nature of the ACTG argue against an emphasis on phase 1 trials, which the committee believes are best accomplished by single ACTU sites, the NIH intramural programs, or experienced pharmaceutical companies.8

Recommendation 3.16: The ACTG should assume primary responsibility for trials that are important to the public health and that are unlikely to be conducted by the pharmaceutical industry. These include trials of drugs in combination, trials that compare drugs made by different companies, trials of drugs for small patient populations such as those with particular opportunistic infections or AIDS-related

8  

Among the ACTG's plans for the near future is the use of contracts for ensuring that phase 1 trials are conducted efficiently.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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cancers, and, in rare instances, phase 4 or postmarketing trials that may not otherwise be conducted. However, the pharmaceutical companies should be encouraged to take responsibility for phase 4 trials of their products, especially those that expand the indications for already approved drugs.

The committee believes that the differing strengths and priorities of NIH and industry provide an opportunity to develop all needed AIDS therapies but that NIH must coordinate its efforts with the private sector to ensure a clear division of labor. Interviews with many NIH officials and representatives of the pharmaceutical industry indicate that the two groups have not yet established a consistently constructive, complementary relationship. Some of the problems with joint NIH-industry trials in the past have included conflicts over the control of protocol design, protocol revisions, IND possession, and data ownership; there has also been outright refusal by many drug companies to work with the ACTG and duplicative efforts between NIH and industry. ACTG officials note that problems involving trials conducted in collaboration with industry have multiplied as the ACTG 's growing workload has forced it, primarily because of lack of staff, to increase its reliance on drug companies for trial management. The high-priority ddI trials are the most notable example of these types of problems. The drug company involved (Bristol-Myers) designed much of the protocol, held the IND, and managed the data. After this arrangement was made, new evidence on the use of low-dose AZT became available, which NIH officials believed necessitated a change in the protocol. It took them several months, however, to convince Bristol-Myers to lower the AZT dosage in the trial.

Industry representatives have several criticisms of the collaborative process used to conduct trials of some AIDS drugs. For example, they assert that NIH does not construct simple, focused trials that concentrate on regulatory approval. This point on the surface is true; obtaining drug approval, however, is not the sole purpose of NIH trials, which often include the broader goal of answers to a wide range of relevant scientific questions. Industry representatives also criticize NIH 's consensus protocol development process as cumbersome, noting that companies lose control over their drug once it enters the ACTG system. Industry officials add that these characteristics of ACTG trials result in fewer opportunities for NIH to test novel antiviral drugs that are being developed by the major drug companies.

As described earlier, the ACTG has undertaken an overly ambitious mission in which it attempts to test every type of AIDS drug at every trial phase. The committee believes that many of the current problems in the NIH-industry relationship will ease as the ACTG focuses its clinical trials mission and undertakes a workload more commensurate with the capacity of its staff and ACTU sites. A reduction of the size of the ACTG's workload will lessen NIH dependence on industry for the trials management services that have created tension between the two sectors. In addition, clear redefinition of the ACTG's mandate to conduct specific types of trials not pursued generally by pharmaceutical firms should lessen duplication.

In redefining the ACTG's role, NIH should recognize that major drug companies, when motivated, are often capable of testing important antiviral agents that have a potentially large market. Industry should be actively encouraged to test such agents (and conduct postapproval studies), and such encouragement should include the recognition by NIH that drug companies will need to overlap with the ACTG in the use of the clinical investigators who are now involved in the ACTU network. Given that the supply of trial participants and qualified researchers is finite, it is essential that the two primary vehicles for conducting these trials (i.e., the pharmaceutical industry and NIH) clearly define their missions and roles and meet regularly to resolve conflicts. The committee believes that NIH-industry collaborations are appropriate and can benefit the development of anti-HIV and anti-OI drugs. The committee also believes that in collaborative

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

ACTG-industry ventures, the ACTG is providing a valuable service and should be appropriately compensated. In such cases the ACTG should negotiate for reimbursement from the pharmaceutical firm and should have control over these funds.

Recommendation 3.17: NIH should ensure maximum coordination of its clinical trials with the pharmaceutical industry by meeting regularly to resolve conflicts over rights to data ownership and access to patients and investigators at ACTU sites. NIH should also negotiate with pharmaceutical companies for supplemental financing of NIH-conducted trials (e.g., postmarketing studies) that clearly benefit the industry sponsor.

Efficiency Within the ACTG

The ACTG has evolved into a 47-center clinical trials network in less than four years owing to an unprecedented infusion of NIH money and staff. Yet as a large applied program that was built rapidly in a crisis environment the ACTG has had little time for long-range planning or evaluation. NIH's initial goals of erecting a trials system and enrolling patients as quickly as possible must give way to a new stage in which the ACTG evaluates its performance and reassesses its administrative procedures and clinical goals. The evaluation 's primary purpose should be to identify inefficient ACTUs in order to take corrective action at unproductive sites and, if necessary, redistribute NIH resources to those trial units that are most productive. (Efficiency is a key issue because ACTUs that enroll very few patients continue to receive full funding, thus increasing the overall trial expenses on a per-patient basis.) A systematic evaluation of trial sites would also provide important information on patient capacities of individual ACTUs to allow better planning of future trials.

The NCI approach to evaluation of its cancer clinical trials groups illustrates several concepts that are relevant to an assessment of the ACTUs. According to NCI officials, the first priority of their evaluation is to identify what is expected of the individual trial units. For example, are the sites meant to enroll patients in the study, to involve underserved patients, to help design protocols, or to perform correlative research on such issues as surrogate markers? Once the mission and expectations for each group are clearly defined, NCI compares a list of actual results with what was expected from each group and assesses the group's performance, allowing for mitigating factors that may explain unmet goals. NCI officials caution that the criteria should be as quantitative as possible to avoid subjective disputes over a site's performance. The NCI evaluation is conducted at three peer-review levels: (1) the cooperative group evaluates its own performance, (2) committees from each regional group evaluate the other groups, and (3) a regional executive committee makes a final assessment of the groups' productivity. To provide close surveillance, evaluation of the cancer clinical trials groups occurs yearly in the context of a noncompeting renewal. The committee believes the ACTG has a strong need for a similar annual evaluation and notes several key principles that should govern its design and implementation. First, NIH must define specific expectations for each of the ACTUs; then a review body, preferably an independent study group consisting of investigators in both AIDS and non-AIDS research, should analyze the ACTUs based on objective criteria. Recently, the ACTG has begun to develop an evaluation program for the ACTUs. Criteria under consideration include the following:

  • number of patients for whom full and accurate data are available;

  • number of minority, IV drug-using, and female patients enrolled in trials (these patients often require more staff assistance);

  • number of patients accrued, adjusted for the difficulty and complexity of a protocol;

  • timeliness and accuracy of data submission;

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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  • scientific contributions of the ACTG site personnel; and

  • coordination by the ACTU with other service organizations (e.g., General Clinical Research Centers, HRSA demonstration projects, and NIDA treatment programs).

To these the committee would add:

  • timeliness of submission of articles reporting research results (see the discussion later in this chapter).

Using these criteria, an expected level of performance and concomitant funding could be determined; superior performance could be encouraged with additional funding or higher priority in the next grant renewal competition. The evaluation process should also provide an opportunity for ACTUs to explain factors that may have adversely affected their performance.

Termination of funding of an ACTU is a complicated, sensitive issue, in part because some ACTUs, in addition to their role in clinical research, are the principal AIDS health care providers in their communities (although it should also be noted that ACTUs that enroll few patients enhance the care of few patients). The committee believes that the primary purpose of an ACTU is to conduct research rather than provide AIDS health care, a view consistent with its conviction that NIH should not have to assume responsibility for providing basic health care (see Chapter 1). NIAID, under the terms of the cooperative agreement that governs its relations with an ACTU, has the prerogative to withhold funding if clearly stated performance goals are not met. This function highlights the importance of an ACTU evaluation that will create data on which to base refunding decisions. The committee believes that the evaluation of ACTUs is an extremely important issue and supports the ACTG's efforts to link performance to funding.

Recommendation 3.18: NIH should conduct an annual, systematic evaluation of each ACTU. The results of these evaluations should be reviewed by an extramural group authorized to advise corrective action and recommend defending of sites that do not meet expected performance standards.

The development and design of AIDS clinical trials are being closely scrutinized by AIDS advocates and the scientific community for sources of inefficiency and potential areas for improvement that might expedite the evaluation of new therapies. At present, the ACTG develops protocols by a multistep consensual process in which ACTU investigators develop a concept and send it through multiple ACTG committees and the Division of AIDS program office for revisions and approval. A common path for a prospective ACTG protocol is depicted in the schema below:

ACTU investigator —> Pathogen Study Group —> ACTG Committee —>

ACTG Executive Committee —> NIAID Division of AIDS —>

Appointment of protocol team —> Revisions (by multiple committees) —>

Local institutional review board approval

During interviews with committee staff, NIH officials noted that one advantage of consensus protocol development was the opportunity for many investigators to contribute to the process and to feel involved in producing the protocols. Yet many ACTG investigators contend that they actually have very little input into the protocols they conduct. NIAID officials acknowledge that the high degree of pluralism in the process causes numerous problems, chief among which is that the many layers of input and review make the process cumbersome and can lead to inordinate delays in opening important trials. Another problem noted by NIH officials is that many investigators often add a test or observation in which they have an individual interest, resulting in

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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protocols that are laden with data requirements pertaining only to a specific investigator but that all ACTUs must satisfy. This aspect of protocol development may produce trials that are unnecessarily expensive and labor intensive.

Despite these problems, however, the committee believes that interaction among the various levels of ACTG investigators and NIH is highly desirable for protocol development. Moreover, the ACTG has played an important public health role in encouraging many excellent investigators to enter AIDS clinical research by offering them opportunities for scientific contribution. Yet the committee also believes that the current ACTG protocol development mechanism is too inefficient. At some point, the ACTG must reduce the degree of pluralism now involved and rely on small groups to write the protocols, unencumbered by layers of review and revision. The committee further believes that if good faith efforts on the part of investigators and the ACTG Executive Committee fail to resolve differences of opinion, there should be a group available (on an ad hoc basis and similar in structure to the present ACTG protocol evaluation subcommittee) to review the protocol and resolve the dispute.

There has also been much recent debate on the appropriate role of the FDA in the development of protocols for NIH AIDS clinical trials. Proponents of proactive FDA involvement, such as ex-FDA Commissioner Frank Young, argue that the FDA can speed drug development by specifying, early in the process, the data that are essential for regulatory approval, which might reduce the amount of data collected and expedite approval of the drug, should it prove efficacious. The main argument for the plan is that the urgency of AIDS trials necessitates early, active dialogue with the FDA to ensure that trial results encounter no unexpected delays in the regulatory process. Although NIH is not a pharmaceutical company bent only on obtaining regulatory approval but also a biomedical research agency interested in answering a broad range of scientific questions, the committee recognizes that early and close consultation with FDA is desirable to expedite future regulatory approval of efficacious drugs; NIH investigators, however, should remain primarily responsible for selecting the scientific questions addressed in ACTG protocols.

Recommendation 3.19: NIH should simplify the ACTG protocol development process while retaining incentives for individual investigator contributions. Small groups of ACTG investigators should assume the decisive role in designing protocols, and NIH should establish a mechanism by which they can receive frequent informal comments and advice from an active, participatory FDA on the data needed for regulatory approval. If the ACTG Executive Committee rejects a protocol that has been so designed, a simple appeals process should be available to resolve the dispute.

The design of ACTG clinical trials has been a frequent source of disagreement both between patients and investigators and within the scientific community itself. The highly complicated clinical nature of AIDS and the large number of ACTG protocols call for simplicity and practicality in trial design. The major concerns noted by patient activists and NIH officials interviewed for this study were that ACTG trials often require excessive data collection and have inappropriately exclusive entry criteria that hinder accrual of participants. The committee commends the ACTG's new protocol evaluation subcommittee, which emphasizes reduced data collection, close examination of entry criteria, and standardization of protocols to make them easier to understand and execute. The ACTG's large burden of trials makes it imperative that protocols focus on a limited number of questions and that the trials do not restrict accrual of patients through unnecessary entry criteria.

Recommendation 3.20: The committee strongly endorses the work of the ACTG's protocol evaluation subcommittee and recommends that its guidelines on optimal

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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protocol design be made available to all ACTG investigators and used as part of NIH's evaluation of proposed protocols.

Accrual

The ongoing shift in the epidemic from gay men to minority populations, current and former users of intravenous drugs, women, and children has stimulated public debate on the feasibility and scientific appropriateness of increasing the representation of these patients in NIH clinical trials. Despite recent progress in minority recruitment, NIH-sponsored AIDS clinical trials include significantly lower numbers of many minority subpopulations with AIDS than their proportions of the infected population would warrant. For example, in New York City, blacks account for 35 percent of all AIDS cases but constitute only 9 percent of ACTG trial subjects.

One reason for the disparity may be that strict entry criteria exclude many patients, including many underrepresented groups, from trials. Restrictive entry criteria for ACTG protocols have been cited by ACTU investigators as a significant factor in slowing the accrual of trials. (An investigator from one New York City ACTU cited an example in which only 3 of 150 screened patients were eligible for an ACTG trial, largely owing to entry criteria.) The committee believes NIH must closely examine the entry criteria it currently employs. As AIDS moves more and more into the subpopulations that are currently underrepresented in NIH clinical trials, these patients increasingly will be the key to swift trial accruals. Furthermore, in a disease with a diversity of patient groups, inclusion in clinical trials of broadly heterogeneous groups of infected people will maximize the applicability of trial results. (For example, biological responses to drugs may differ in certain populations such as former and current users of intravenous drugs, women, and children.) The committee believes the NIH clinical trials have an ethical responsibility to obtain results that apply to all patient populations, although not all phases of clinical trials require representativeness. Some clinical trials, particularly phase 1 trials that focus on dosage and adverse drug effects, can be conducted on a narrow or homogeneous spectrum of the patient population and still yield useful results. In contrast, trials in phases 2 through 4, which focus on efficacy and rare reactions, favor inclusion of a broader, more diverse group of patients.

Because clinical trial participants, particularly in the earliest phases of the study of a drug, expose themselves to significant physical risks as well as potential benefits, the committee does not subscribe to the belief that right of access to a clinical trial can be equated with a patient's right to medical care. In phase 2–4 trials of AIDS drugs, however, there is a greater potential for clinical benefit. Therefore, although the primary purpose of the trials is not to provide treatment, they do serve that function.

The committee considers it essential that NIH improve its recruitment of minority populations, women, children, and intravenous drug users as participants in clinical trials. There are steps that NIH could and already is planning to take to improve recruitment and retention of underrepresented populations, such as providing obstetrical, perinatal, and ancillary services for women in trials. But some of the difficulties encountered by NIH-supported trials in their efforts to enhance recruitment are by-products of the much larger set of problems posed by this country's health care delivery and financing systems (see Chapter 1). The committee recognizes NIH's recent efforts to engage health professionals in outreach activities among the populations that are currently underrepresented in clinical trials (with the goal of hastening accrual) and encourages further measures, such as less stringent entry criteria, that might speed trial accrual among all infected populations. It also commends the work of the newly established Community Program for Clinical Research on AIDS for its efforts to include underrepresented populations.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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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

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

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.

Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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Suggested Citation:"3 Elements of the NIH AIDS Research Program." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
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This book, written at the request of the National Institutes of Health (NIH) to assist its AIDS program office in planning future directions, contains a series of recommendations for ensuring that AIDS research is a well-organized, well-planned, and comprehensive long-range program leading to the control and eventual eradication of the disease. The recommendations are intended to strengthen the planning, evaluation, and coordination of AIDS research activities; ensure their quality and cost-effectiveness; stimulate further development of promising research areas; increase the level of support for AIDS research so that researchers can carry out a comprehensive program; and provide the personnel and facilities at NIH needed to conduct and manage an effective, efficient AIDS research program.

The book also identifies barriers in the delivery and financing of health care that are outside NIH's responsibility, but that adversely affect its AIDS clinical research efforts, and urges federal action to eliminate them.

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