The AIDS Research Program of the National Institutes of Health (1991) / Chapter Skim
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3 Elements of the NIH AIDS Research Program
3 Elements of the NIH AIDS Research Program
Pages 53-94
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From page 53... ...
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.
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From page 54... ...
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 retrovimicPc Anna h^`z7 the cna r~r~r`tr~r r^^r`~;~7~ Stan =~' envelope protein ~, ~~ ,^~___~ Ace_ ,^~, Ace_ _~ &_~V1 A—~~ Ally 111 ~ — .r 1 ~ · National Cancer Institut~NCI supports the next largest basic AIDS research program at NIH, much of it intramural.
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From page 55... ...
To date, the NIH AIDS research program has emphasized directed research, primarily in largescale 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.
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From page 56... ...
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 precl~nical 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 teals at the AIDS vaccine evaluation units supported by NIH.
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From page 57... ...
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.
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From page 58... ...
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.
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From page 59... ...
(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 win increase the number of trial participants required.
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From page 60... ...
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.
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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 (SFbiIHS)
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From page 62... ...
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 [actors associated with vertical transmission, and the effect of HIV disease on the health status of the newborn.
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From page 63... ...
-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 over50 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.
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From page 64... ...
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 Cu~Tently, 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.
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From page 65... ...
NIH must also identity 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.
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From page 66... ...
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.
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From page 67... ...
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.
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From page 68... ...
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.
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From page 69... ...
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)
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From page 70... ...
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.
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From page 71... ...
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.
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From page 72... ...
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, NLAID, and NIGMS.
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National Institute of Allergy and Infectious Diseases NL\ID supports preclinical drug discovery and development initiatives for HIV and opportunistic infections in three general areas: (1) targeted drug development, (2)
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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.
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. NLAID 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: - GO _ _~_ · Pneumocystis canny pneumonia—there is still debate as to whether the pathogen is a protozoa or a fungus; moreover, it cannot be cultured in vitro.
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From page 76... ...
NIH should also facilitate the development of promising drugs for opportunistic infections through all the steps necessary to secure the IND application. CLINICAL TRILLS A major goal of the AIDS research program is the development for clinical use of treatments for HIV infection and the diseases it causes.
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Mission of the AIDS Clinical Trials Group One of the major questions confronting NIH's AIDS clinical research program is how it dehlnes the mission of the ACIG. Many of the NIH officials interviewed by the committee said that lack of a clear mission was the cause of many of the AC[G's current problems, in that the ACIG undertook more trials than its staff and clinical resources could handle.
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From page 78... ...
The large size and multicenter nature of the ACING argue against an emphasis on phase 1 trials, which the committee believes are best accomplished by single ACID 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 Among the ACIG's plans for the near future is the use of contracts for ensuring that phase 1 trials are conducted efficiently.
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From page 79... ...
79 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.
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From page 80... ...
First, NIH must define specific expectations for each of the ACI~Us; then a review body, preferably an independent study group consisting of investigators in both AIDS and non-AIDS research, should analyze the ACIIJs based on objective criteria. Recently, the ACIG has begun to develop an evaluation program for the ACTUs.
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From page 81... ...
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.
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From page 82... ...
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.
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From page 83... ...
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 ACT G trial subjects.
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From page 84... ...
· 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)
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From page 85... ...
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.
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From page 86... ...
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.
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From page 87... ...
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)
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From page 88... ...
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.
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From page 89... ...
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/HWExpenmental 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.
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From page 90... ...
Other NIH components besides NLAID 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.
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E' FMENTS OF WE NIH AIDS SUCH Pats 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 National Heart, Lung, and Blood Institute National Cancer Institute National Institute of Child Health and Human Development Fogies International Center National Institute of Dental Research National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institute on Aging National Center for Nursing Research Total 71,500 18,290 16,663 15,017 2,938 550 320 274 241 125,793 .
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by Institute 1988 1989 1990 1991 Institute Dollam Percent Dollars Percent Dollars Percent Dollarsa Percent NC! 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 74 118,354 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 NIODK 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 Oen:~t Row= N WE Nat 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.
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From page 94... ...
NCNR, Priority Expert Panel on HIV Infection.
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