National Academies Press: OpenBook
« Previous: Front Matter
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×

Summary

AIDS: THE RESEARCH CHALLENGE

In the 1980s the National Institutes of Health (NIH1) faced an unprecedented challenge in responding to the epidemic of human immunodeficiency virus (HIV) infection and the acquired immune deficiency syndrome (AIDS), modern biology's first pandemic of a new, deadly infectious disease. Once the magnitude of the epidemic became clear–especially once HIV was identified as the causal agent –NIH was given the mandate and resources to develop a large, multifaceted AIDS research program to understand the virus's pathogenesis, discover and test therapies, and develop prevention strategies and a vaccine. Research supported and conducted by NIH has led to rapid increases in basic knowledge about HIV and its replication, the molecular and behavioral aspects of transmission, the human immune response to HIV infection, and the clinical course of AIDS. Researchers have discovered and developed some partially effective therapies, and recent advances in vaccine research have convinced many scientists that an effective vaccine may someday be available. Meanwhile, however, the epidemic continues to grow and spread to new areas and populations, trends that argue for a well-planned, well-organized long-term research program leading to the control and eventual eradication of the disease.

The committee concludes that NIH should continue to give AIDS research high priority because HIV infection and AIDS constitute a major public health threat and because they provide substantial opportunities for greater scientific understanding of the human immune system and of other viral diseases. The size and long-term nature of the threat call for an institutionalized response by NIH.

Recommendation 1.1: NIH should complete its building of the AIDS research program as a comprehensive, long-term effort. The shaping and implementation of such a program will require a series of steps that are described in the remainder of this report.

These steps should have several positive results: strengthened management structures and processes for planning, coordinating, evaluating, and reallocating the AIDS research activities supported by the various NIH components and for ensuring their quality and cost-effectiveness; fuller development of some promising research areas; an increased overall level of support for

1  

See Appendix D for a complete list of abbreviations and acronyms.

Suggested Citation:"Summary." 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; and increased personnel and facilities resources to enable NIH to conduct and manage an effective, efficient AIDS research program.

Although the committee was not asked to address health care issues, it could not avoid the finding that NIH-sponsored research on HIV infection and AIDS has been hampered by inadequate participation in clinical trials of some high-incidence groups whose members are not insured for and are unable to pay for treatment or associated medical care. This lack of coverage of some high-incidence populations is part of the larger problem of health care delivery and financing for persons with AIDS, a problem that looms ever larger as more and more individuals acquire the disease in the near future. The committee believes that NIH's mandate is to facilitate the discovery and clinical evaluation of therapeutic, diagnostic, and preventive agents and not to assure health care. This problem must be addressed at more appropriate levels of the federal health policy-making establishment.

Recommendation 1.2: The Health Care Financing Administration (HCFA) should make its reimbursement policies consistent with NIH assessments of promising treatments so that when treatments have moved beyond phase 1 testing, their associated medical care costs (and the costs of the treatment if the sponsor is unable to provide it free of charge) are covered for Medicare and Medicaid beneficiaries.

Changing HCFA policies to cover treatment and other medical care costs associated with research is only part of the solution to the problem of caring for HIV-infected persons. A more comprehensive approach to financing such care will be needed to eliminate barriers to participation in AIDS/HIV clinical research and to ensure that the improved therapies that emerge from federally supported research are available to those who need them.

Recommendation 1.3: The administration and Congress should immediately address and resolve financial barriers to the receipt of appropriate medical care by persons with HIV infection.

MANAGING THE NIH AIDS RESEARCH PROGRAM

HIV and AIDS are not solely challenges faced by physicians and scientists. The management of NIH has also been presented with an unprecedented task in developing, implementing, coordinating, and evaluating a rapidly growing, complex set of AIDS research activities that now involve every NIH institute, center, and division.

AIDS research at NIH is unusual in that it is not organized under an institute as are, for example, cancer research, vision research, and research on cardiovascular diseases. Instead, NIH is managing the AIDS research program as an “institute without walls,” operating the AIDS program from the Office of the NIH Director but using organizational elements analogous to those of the institutes. These elements include a director (the associate director for AIDS research), a national advisory council (the AIDS Program Advisory Committee), an executive committee of senior program officials (the NIH AIDS Executive Committee), and an executive office for staff support (the Office of AIDS Research, or OAR). The committee believes these organizational arrangements and associated administrative processes for managing AIDS research should be strengthened, as an alternative to creation of a separate AIDS institute, and institutionalized as a major long-term program at NIH.

Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Strengthening Planning and Evaluation
Planning

Because of the large size and organizational complexity of NIH's AIDS research enterprise, the committee believes program management as well as program effectiveness would be improved by the development of an overall long-range research plan. The plan should set out the program's goals and assign priorities. It should define the resources required and the mechanisms to be used and identify the results that are expected over specific time periods. The plan also should be flexible to allow prompt adaptation to unanticipated events that alter prior assumptions. Consequently, it should be subject to periodic review and should be revised annually through a formal decision process.

Recommendation 2.1: NIH should develop a five-year plan to identify AIDS-related research needs and opportunities, set priorities, assess program balance, identify research areas that need stimulation, determine the resources required to carry out the program, and evaluate progress. The plan should be developed under the auspices of the AIDS Program Advisory Committee (after the committee is expanded and oriented as recommended below), with the input of outside experts as well as OAR staff, and it should be reviewed and updated annually. The annual plan review should occur in time to guide the preparation of the regular annual budget so that responsibilities and resources can be shifted if appropriate.

Evaluation

Until recently the rapid budgetary growth of the AIDS program has driven the planning process, rather than the reverse. Most of NIH 's AIDS research activities were hurriedly launched by limited staff in the mid-1980s, years of substantial budget increases. As the program matures, however, attention is turning appropriately to the relevance, effectiveness, and efficiency of ongoing activities. Until now, NIH has relied on its time-honored method of evaluation and quality control: peer review of research applications by study sections of independent experts. Many AIDS grants, however, involve large, multidisciplinary projects, centers, and cooperative groups that are closely related to an institute's categorical mission. Scientific review of these projects is essential, but insufficient, because administratively they pose quite different questions of efficiency, effectiveness, and productivity than projects involving an individual investigator in a lab. The situation calls not only for stronger program planning but for stronger evaluation efforts and close linking of planning and evaluation results to the budget allocation process.

Recommendation 2.2: AIDS program evaluation processes should be strengthened and linked closely to planning and budgeting processes to ensure that, first, questions of the highest priority are addressed adequately at all times; second, all studies being supported are still relevant and are as productive and efficient as possible; and third, resources are redeployed, sometimes across institutes, in response to research advances and breakthroughs or as time and experience indicate that some programs are more and some less successful than others in achieving their goals. The Office of AIDS Research should work closely with the Division of Planning and Evaluation in the NIH Director's Office to coordinate evaluations of AIDS research programs in the various institutes. In turn, evaluation results should be considered in program planning and budgeting.

Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Strengthening External Advisory Processes

One of NIH's strengths is its ability to incorporate external advice from scientists and the public in its planning and operations. As in its other research programs, NIH has established advisory groups at every level of the AIDS research program; many of these groups include patient advocates and members of the general public as well as scientists and researchers. The associate director for AIDS research should routinely reevaluate the need for such committees as the AIDS research program is institutionalized as a long-term activity over the next several years. Not in question is the need for a high-level advisory function, and the committee urges NIH to strengthen its processes for external advice on overall issues of level of effort, balance among research areas and mechanisms, and research opportunities and needs in the AIDS research program. This high-level advisory function, which national advisory councils fulfill in relation to the institutes, should be the role of the AIDS Program Advisory Committee (APAC). APAC has a critical role to play in providing broad advice and overall program oversight; it should also oversee development of the long-term AIDS research plan and ensure extensive external input.

Recommendation 2.3: The AIDS Program Advisory Committee should take a larger role in providing broad policy advice and program oversight and should include among its activities the development of the five-year AIDS research plan and annual updates. It should also conduct an annual review of the programs and budgets developed to implement the plan. This expanded role will require additional staff support and a larger committee to ensure that all AIDS-related areas of expertise are represented, including the behavioral and social sciences and public health authorities. It may also require the establishment of additional subsidiary committees and the recruitment of additional outside experts to review the various research areas (e.g., basic, behavioral, epidemiological).

Strengthening Staff Support

The expanded roles of the associate director for AIDS research and the AIDS Program Advisory Committee in planning, evaluation, and budgeting will require some additional staff support by the Office of AIDS Research and related units in the Office of the NIH Director. In most areas of the AIDS research program, the associate director for AIDS research and the OAR will coordinate activities that are actually carried out by the institutes, centers, and divisions; in other areas–planning, implementing, and evaluating certain cross-cutting functions such as training and construction programs–they should play a larger role. In addition, as recommended later, OAR should review and approve (in accordance with assigned priorities in the overall plan for research) AIDS-related requests for applications (RFA) and requests for proposals (RFP) initiated by the individual institutes.

Recommendation 2.4: The capacity of the Office of AIDS Research should be increased so that it can function adequately as the staff arm of the associate director for AIDS research in his or her role as leader and coordinator of the AIDS program. In particular, OAR will need some additional planning and evaluation staff, including several senior-level scientists who can assist the associate director for AIDS research and the AIDS Program Advisory Committee in monitoring the AIDS research agenda, assessing progress, identifying scientific gaps that need to be addressed, and coordinating the review of institute research initiatives.

Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Strengthening Executive Authority and Flexibility

The AIDS program is the first major research program to be managed by the Office of the NIH Director rather than by a single institute. The committee considered and rejected the option of creating a separate National Institute of AIDS Research because it believes that the involvement of multiple institutes in addressing the complexities of AIDS will speed scientific progress. Most, if not all, of the advantages of putting the program under one institute–improved communication, management, priority setting, and accountability–can be achieved by the adoption of the strengthened management system, based in the Office of the Director, that is recommended in this report. Thus, in addition to comprehensive, long-range planning and evaluation of AIDS research, the capacity of the NIH Director's Office to implement and coordinate AIDS research activities should be augmented.

Recommendation 2.5: The director of NIH should be given an adequate annually renewed discretionary fund of at least $20 million along with additional authority to transfer up to 1 percent of each NIH appropriation account to increase the agency's flexibility in responding to future emergencies or research opportunities. These resources could be used to exploit important scientific breakthroughs arising in AIDS or non-AIDS research that could not be anticipated in the regular budget process or to address major epidemics or other public health problems that suddenly emerge.

The committee is convinced that an important component of the current strength and success of the NIH AIDS research program is the unique leadership provided by Anthony Fauci, associate director of NIH for AIDS research and director of the National Institute of Allergy and Infectious Diseases (NIAID). Having the same person as director of NIAID, which receives nearly half the NIH AIDS budget, and associate director for AIDS research is administratively unorthodox, because it poses potential conflict of interest problems when questions of interinstitute coordination, budget allocation, and program jurisdiction arise. Each of the positions is also extremely demanding, an aspect that, in the case of the position of associate director for AIDS research, will only intensify if the AIDS program structure is strengthened and institutionalized, as recommended in this report. In this instance the arrangement has worked well because of the energy, knowledge, even-handedness, and prestige of the incumbent.

Recommendation 2.6: The current arrangement of the same person holding the positions of both associate director for AIDS research and director of NIAID is working well. Nevertheless, because of the already substantial and still growing workload of each position, and the potential for bias in mediating conflicts among institutes, the committee believes that the joining of these positions should be reconsidered at such time as the current incumbent steps down.

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 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 Chapter 3,

Suggested Citation:"Summary." 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 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 also offers specific conclusions and recommendations regarding the mission, design, size, and management of each component.

Basic Research

The 1980s have seen several major advances in research on AIDS–for example, identification of the causal agent, HIV; development of diagnostic tests for HIV infection; and progress in vaccine and drug development. Such advances have been, and will continue to be, based on fundamental knowledge and methods derived from basic, undifferentiated research that predates the advent of the AIDS pandemic. 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 diseases 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.

Vaccines

Recent advances in HIV vaccine research give considerable cause for optimism about prospects for an HIV vaccine, although many scientific obstacles remain to be overcome. This progress, given the enormous benefit of a successful vaccine for prevention of HIV infection, warrants vigorous expansion of the HIV vaccine program. In order to pursue as many promising research avenues as possible, including those not fully explored by the individual investigator-initiated mechanism, strong support of 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 RFAs and RFPs that target the essential unanswered immunological questions.

The committee considered and rejected recommending a centralized approach to vaccine research because it is premature to focus on a particular approach. The many remaining scientific obstacles to an AIDS vaccine argue for support of diverse research efforts such as those currently being pursued by the various institutes within NIH, together with a mechanism to preclude the inefficient use of resources.

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 simian immunodeficiency virus (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 industry.

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

If and when attractive candidates for vaccines emerge, the clinical trials that must be conducted to establish their efficacy will be logistically difficult, requiring considerable planning. Problems include liability concerns, developing criteria for placing an HIV vaccine candidate into phase 3 efficacy trials, and selecting trial participants.

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.

Other major barriers to producing a viable candidate vaccine are a shortage of animal models (especially nonhuman primates), a lack of suitable containment facilities (i.e., facilities rated at biosafety levels 2 and 3) for housing animals and conducting HIV or SIV vaccine research, and a lack of reagents. Recent studies demonstrating protection against infection with the SIV model are cause for optimism regarding an HIV vaccine and warrant increased support for further animal-model studies (see recommendations 3.28 and 3.29). 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 or by 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 high-quality reagents has hindered HIV vaccine research. They also said that investigators do not always provide other scientists with access to reagents developed with NIH support.

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.

Epidemiology

NIH conducts and supports a number of epidemiological studies that in the past have provided invaluable knowledge about the natural history, transmission, clinical markers, and cofactors of HIV infection and the advent and course of AIDS. Information from these studies provided the foundation for a range of NIH AIDS research efforts, including the design and conduct of clinical trials of therapeutic agents against HIV and associated opportunistic infections

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

(OI) and cancers. In the future, epidemiological studies will be especially important in identifying populations suitable for large-scale vaccine efficacy trials. Yet as the disease changes (e.g., in the appearance of opportunistic infections, in the groups affected) and responds to new treatments, the additional insights to be gained from existing cohorts may not justify the costs of data collection and analysis. NIH's epidemiological AIDS research component 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.

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.

To maximize the use of resources and prevent the initiation of cohorts of insufficient size to enable meaningful statistical analysis, NIH should also identify opportunities for collaboration, both among institutes and with other Public Health Service (PHS) agencies involved in epidemiological research (the Centers for Disease Control [CDC] and the Alcohol, Drug Abuse, and Mental Health Administration [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 HIV/AIDS epidemic is both a biological and a behavioral phenomenon, and efforts to contain its spread must look to both biomedical and behavioral sciences for interventions. The committee believes NIH has neglected AIDS-related behavioral research. 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.

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.

The AIDS epidemic has highlighted the need for up-to-date data that are representative of the general population and that can provide a sound basis for designing, implementing, and evaluating education and intervention programs to stop the spread of HIV. In an effort to expand this data base, the National Institute of Child Health and Human Development (NICHD) has

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

proposed a national survey of health behaviors and AIDS risk prevalence, but plans for the survey have not been approved by the Department of Health and Human Services because of concerns about the survey 's scope and content.

Recommendation 3.10: The pretest questionnaire for NICHD'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

The committee believes that high-quality care of persons with AIDS, and management of the side effects of AIDS therapeutics, will be essential to ensure a reasonable quality of life for persons who are living with HIV infection. The committee also believes that the knowledge base in this area 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.

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

Preclinical Drug Development

Preclinical drug development of anti-HIV agents and agents for related opportunistic infections is supported by both NIH and the pharmaceutical industry. The different groups that have shown interest in developing anti-HIV drugs possess varying levels of resources for conducting the critical studies required by the Food and Drug Administration (FDA) for an investigational new drug (IND) application to permit use of the drug on a broad scale. The National Cancer Institute' s (NCI) long experience in developing therapies in collaboration with drug companies and academic health centers has provided valuable lessons for organizing the development and clinical testing of new AIDS drugs. The committee believes NIH should focus its AIDS-related drug development resources on promising drugs that would not otherwise be developed by the pharmaceutical industry, and on assistance for drug sponsors that do not possess adequate resources to complete the studies required for submission of an IND application.

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.

Both biochemical and cell-based drug screens are necessary to identify agents with differing mechanisms of action against HIV as well as agents active against discrete components of the HIV life cycle. NIH support for mechanism-of-action studies is particularly important because such studies are unlikely to be conducted by industry.

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.

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

An underdeveloped basic science knowledge base and lack of suitable animal models for many of the OIs that commonly occur in people with AIDS have hindered drug development efforts. Support by the pharmaceutical industry for basic science and animal model studies related to OIs is unlikely. The committee concludes that NIH should have the capacity to conduct this research and 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

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:

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

  • establishment of a national clinical trials program 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 infection 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 information about treatment with a wide array of antiviral and anti-OI drugs.

Mission

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. To begin with, NIH must define the AIDS Clinical Trials Group's (ACTG) mission more clearly with a realistic statement of its scientific goals.

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 the 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.

Suggested Citation:"Summary." 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 3.16: 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 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.

Interviews with many NIH officials and representatives of the pharmaceutical industry indicated that the ACTG and the industry have not yet established a consistently constructive, complementary relationship. Given that the supply of trial participants and qualified researchers is finite, it is essential that the two primary vehicles for conducting 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.

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 AIDS clinical trials unit (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

NIH's initial goals of erecting a clinical trials system and enrolling patients as quickly as possible is giving way to a new stage in which the ACTG evaluates its performance and reassesses its administrative procedures and clinical goals. The committee recognizes and endorses the ongoing effort at the Clinical Research Management Branch of NIAID's Division of AIDS to develop a mechanism and criteria for evaluating individual ACTUs as a basis for planning future trials and for ACTU refunding in 1991 and 1992.

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 defunding of sites that do not meet expected performance standards.

At present, the ACTG develops protocols by a multistep consensus 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. The committee believes that the large number of ACTG trials has combined with the multiple revisions and steps required in its protocol development process to overload the ACTG system and slow the opening of important new trials.

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

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

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.

To address and resolve the many problems involved with protocol design, the ACTG established a protocol evaluation subcommittee.

Recommendation 3.20: The committee strongly endorses the work of the ACTG's protocol evaluation subcommittee and recommends that its guidelines on optimal protocol design be made available to all ACTG investigators and used as part of NIH's evaluation of proposed protocols.

Accrual

The committee considers it essential that NIH improve its recruitment of minority populations, women, children, and intravenous drug users for clinical trials. The committee recognizes NIH's efforts to engage health professionals in outreach activities among populations that are currently underrepresented in the trials (with the goal of hastening trial accrual) and encourages further measures, such as less stringent entry criteria, that might speed trial accrual among all infected populations.

Recommendation 3.21: The committee believes NIH should increase participation of currently 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

Interinstitute sponsorship of clinical trials can bring a wide variety of expertise and resources to bear on difficult scientific questions. However, the interinstitute conflict that frequently accompanies such sponsorship may hinder NIH's ability to maximize its resources. Instances of unresolved conflicts surrounding the sponsorship and funding of trials highlight NIH's need for a stronger mechanism to resolve interinstitute disputes and implement necessary changes, as recommended in Chapter 2. In the case of interinstitute coordination of pediatric AIDS clinical trials, the committee believes unresolved conflicts have prevented a fully operational merger of NIAID's and NICHD's pediatric trial systems.

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.

The committee believes that the intramural clinical trials programs at NCI and NIAID possess excellent researchers and resources that have allowed them to achieve important advances in the development of new AIDS therapies. Moreover, the close proximity of intramural laboratories to clinical programs at the NIH clinical center promotes rapid in vivo testing of in vitro results.

Suggested Citation:"Summary." 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 3.23: NIH should continue to provide strong financial support for AIDS research efforts of the intramural clinical trials programs.

The committee is concerned, however, that NIH does not have a clear track for bringing a drug through all stages of clinical testing and has not sufficiently capitalized on its intramural program for the execution of certain trials.

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 rapidly. The committee believes NIH has an obligation to publish all such results, whether the trial has a positive, negative, or indeterminate conclusion, because the publication process is the primary means for expanding the knowledge base. The committee strongly endorses the use of expeditious peer review and publication as the best method of information dissemination but recognizes that alternative, faster means may be needed for certain clinically relevant trials.

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

Research resources, a public “good” for which federal support is especially suited, are investments in the infrastructure of biomedical science that help researchers do their work quickly and economically. The importance of such resources increases as the AIDS research program becomes a long-term effort.

Training

Research training is an integral part of NIH's multi-institute AIDS research program. Planning and implementation of training activities should be administered centrally by the associate director for AIDS research with staff assistance from the OAR.

Suggested Citation:"Summary." 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 3.27: 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 the National Institute of General Medical Sciences (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, recent demonstrations of prophylactic and postinfection protection from disease in the SIV-macaque model hold 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

Inadequate facilities will hinder scientific efforts and could pose unnecessary dangers for AIDS researchers. In the committee's view, support for upgraded facilities and equipment is an appropriate element in a balanced, long-term AIDS research program, especially during initial expansion years.

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

In addition to the dissemination of trial results, NIH supports an extensive AIDS communications program for scientists, health providers, patients, and the general public. (Research advances with implications for prevention, diagnosis, and treatment are raising new and urgent questions about early dissemination, which were addressed in the section on clinical trials [recommendations 3.25 and 3.26].) The committee commends this work but encourages NIH to solicit input from the

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

public and the scientific community on its efforts and periodically to review its programs in this area.

SUPPORTING THE NIH AIDS RESEARCH PROGRAM

The success of the NIH AIDS research program depends critically on adequate, high-quality resources to support the program's efforts. These resources include funds for the research itself, in the form of grants, contracts, and intramural projects, and for research infrastructure –research training programs and facilities and equipment grants. Research resources also include NIH's apparatus for reviewing research grant and contract applications and proposals for technical merit and program need, as well as the agency's own staffing and facilities.

Funding of AIDS Research

The committee reviewed carefully the size and composition of the NIH AIDS budget, aware of a general perception that the epidemic is receding and that the current level of effort is adequate. The committee finds, however, that the epidemic of HIV infection and AIDS remains a severe global public health emergency that is causing a growing burden of illness and death and placing severe stresses on the nation's health care system. At present there is no cure for the disease and no vaccine. Containment, therefore, must be a high national priority, and more effective interventions are urgently needed.

As a comprehensive, long-term effort, the NIH AIDS program must respond in a balanced way to knowledge gaps, emerging scientific opportunities, changes in the epidemic, and other, unforeseen contingencies. The question of program balance is thus an evolving one that should be addressed through the planning and priority-setting process recommended in this report. For example, promising scientific developments in vaccine research urge additional studies, which will require more funds for grants and research resources. In addition, a balanced, long-range program should invest more in undirected individual investigator-initiated research, given the lack of basic knowledge about HIV infection and AIDS. The benefits to be derived from such research often go well beyond those applicable strictly to HIV/AIDS. Scientific advances in AIDS research also will continue to have important spinoffs that contribute to progress against other diseases and provide a base of knowledge that will be useful in dealing with epidemics of the future.

The committee concluded that other areas of AIDS-related research are relatively underdeveloped and should be expanded; these include behavioral research, nursing research, development and testing of therapies for AIDS-related OIs and cancers, and research training. On the other hand, greater efficiency may be possible in some of the large-scale programs that have been running for several years or more, such as epidemiology and clinical trials. In the opinion of the committee, increased management efforts and program activity in a number of areas would not be adequately accommodated within the present level of effort. The net effect of the committee's recommendations could increase costs on an order of magnitude of 25 percent, a rough estimate that might be lowered (if there were significant savings in existing activities) or raised (if there were major breakthroughs that required exploiting).

The committee is aware that many people consider the NIH budget as a whole to be inadequate and that there is an immediate crisis in funding a sufficient number of competing grants this fiscal year and next to maintain the nation's biomedical research momentum. The committee is also aware that advances in containing and controlling AIDS rest on the overall strength of the

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

NIH units. Taking resources from other parts of the agency to expand the AIDS research program would impede overall progress in biomedical research and the AIDS program itself, which is an integral part of and dependent on a wide range of NIH activities.

Recommendation 4.1: Implementing the long-term AIDS research program recommended by this committee will require a larger budget to ensure that the most promising basic science opportunities are supported, that underdeveloped areas of research are expanded, and that research resources are adequate to support the planned level of research effort. These opportunities and needs could justify an immediate increase of as much as 25 percent in NIH's budget for AIDS research; the exact timing of the increase should be an integral part of the long-range plan recommended by the committee. It is essential that any such budget increases be new funds and that they not be derived at the expense of ongoing NIH programs.

In the past, NIH defined AIDS research narrowly to encourage well-established researchers to leave research in other areas for studies on AIDS. This goal has now been achieved, and the artificial distinction between AIDS research and AIDS-related basic research has outlived its usefulness.

Recommendation 4.2: NIH should adopt NIAID's recent redefinition of AIDS research (to include closely related basic research in immunology, virology, molecular biology, cellular biology, and other related areas) for use throughout its institutes.

Grants Policy and Administration

The committee has carefully examined NIH's organizational and procedural arrangements for reviewing and awarding AIDS-related research grants and concludes that currently they are adequate. AIDS research project grant applications and awards have increased in number and improved in quality, as measured by peer-review scores. The share of the AIDS budget going to research project grants has increased to about 40 percent, and the proportion of those solicited by RFAs has decreased. The committee recognizes the need for solicited research and directive mechanisms in building a fast response to a public health emergency but believes that a long-range AIDS research program warrants greater reliance on grants, especially individual investigator-initiated grants.

Recommendation 4.3: NIH should continue to increase its use of research grants, especially traditional individual investigator-initiated and related grant mechanisms, to carry out the expanded research effort recommended by the committee, in particular, the increased effort in basic research.

RFAs and RFPs at NIH are usually initiated by program staff who identify gaps in research and propose mechanisms for soliciting grant applications to address those gaps. After approval at the institute and advisory council levels, proposed RFAs and RFPs receive an administrative review in the Office of the NIH Director and are circulated to the other institutes for comment and to minimize duplication of effort. The committee believes that central review of RFAs and RFPs should be coordinated with the research planning effort recommended in Chapter 2 of the report to identify and remedy gaps in AIDS research.

Recommendation 4.4: The NIH associate director for AIDS research and the AIDS Program Advisory Committee should review all RFAs and RFPs for AIDS research to

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

ensure coordination and avoid duplication. They should also have the authority to recommend RFAs and RFPs in the case of gaps in the NIH AIDS research program that are not being addressed by individual institutes.

Administrative Support

The effectiveness and success of the NIH AIDS extramural and intramural research programs depend in part on the adequacy of the administrative support they receive in the form of staffing and facilities.

Staffing

Until recently, NIH operations were hampered by arbitrary personnel ceilings imposed by the Office of Management and Budget (OMB). These ceilings had a significant effect on the AIDS research program because the number of scientists and science administrators could not increase as quickly as the scientific opportunities for intramural AIDS studies or the amount of funding for extramural AIDS grants and programs. Chronic understaffing thus has constrained NIH's ability to conduct AIDS research and adequately plan, administer, and evaluate its extramural AIDS programs. Now, however, OMB and the Department of Health and Human Services (DHHS) have delegated increased authority to PHS agencies to set personnel levels. NIH in turn must determine appropriate program staffing and develop a plan to achieve it.

Recommendation 4.5: The committee strongly opposes arbitrary restrictions on NIH staffing levels that are established without regard to program requirements because they hamper effective, efficient management. Personnel ceilings should be abandoned permanently, and future staffing decisions should be part of the strengthened program planning and budgeting processes recommended in Chapter 2 and coordinated by the Office of the NIH Director. Adjustments in staffing levels should be made carefully over several years to achieve appropriate balances between AIDS and non-AIDS programs, between the elimination of past deficits and the needs of new initiatives, and between the budgets for extramural grants and contracts and for staff to administer those grants and contracts.

The committee also supports efforts to maintain NIH staff excellence by addressing broader personnel problems, both those relating to compensation and those stemming from inflexible or sluggish policies and procedures of government personnel systems. The committee endorses as well special efforts to solve problems specific to the AIDS program, such as recruitment and retention of medical officers in the NIH AIDS treatment research (clinical trials) program.

Facilities

NIH-wide space limitations and inadequacies have affected the AIDS research program disproportionately because it is a relatively new and fast-growing set of activities. Congress's appropriations over the past several years for buildings and facilities have greatly reduced the backlog of needs for adequate, appropriate space and equipment for AIDS research, but much of this capacity is in off-campus sites. The committee believes that the scattered locations of AIDS activities hamper communication and collaboration between AIDS basic and clinical researchers and between AIDS and non-AIDS researchers involved in related studies; they also impede administra-

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

tive coordination of extramural AIDS and AIDS-related research programs in the different institutes, centers, and divisions.

Recommendation 4.6: As part of its long-range building and facilities program, NIH should consolidate AIDS research and research administration on the NIH campus. This consolidation will facilitate communication between the intramural and extramural programs and coordination of the multiple institutes, centers, and divisions involved in AIDS research activities. The committee endorses NIH's effort to take a systematic, sustained approach to upgrading and maintaining the campus infrastructure, which will benefit the AIDS program as well as non-AIDS research.

Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 1
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 2
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 3
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 4
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 5
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 6
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 7
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 8
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 9
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 10
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 11
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 12
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 13
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 14
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 15
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 16
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 17
Suggested Citation:"Summary." Institute of Medicine. 1991. The AIDS Research Program of the National Institutes of Health. Washington, DC: The National Academies Press. doi: 10.17226/1769.
×
Page 18
Next: 1 AIDS: The Research Challenge »
The AIDS Research Program of the National Institutes of Health Get This Book
×
Buy Paperback | $45.00
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

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.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!