John Y. Killen, M.D., Director, DAIDS
The meeting which was held in the Natcher Conference Center on the campus of the National Institutes of Health, was chaired by Dr. Marian R. Neutra, Chairperson of the AIDS Research Advisory Committee (ARAC).
Report from the Director: Dr. Jack Killen
Dr. Killen welcomed everyone to the meeting and announced several staff changes, including his own departure from the Division of Acquired Immunodeficiency Syndrome (DAIDS). Dr. Killen said that he would remain at the Division in his capacity as Director until another Director has been recruited. Recruitment efforts are currently underway. He noted other staff departures and additions, and reported that Dr. Giorgi is the new liaison to the Office of AIDS Research Advisory Committee.
Budget Update: Congress has not acted on the President's proposed budget for FY 2000 since the last committee meeting; however, Dr. Killen reviewed the President's proposed budget, which only included a 2.4% increase for the NIH. Under that scenario, he described NIAID's preliminary financial management plan, particularly with respect to how NIAID would maintain a payline at the twentieth percentile. Dr. Killen did note Congress's support for biomedical research in Congress and indicated that the actual budget might in fact be very different.
Scientific Update: Dr. Killen highlighted some of the most significant scientific findings resulting from NIAID-sponsored research during the past year. Most notable was the identification of Nevirapine as an effective means of reducing mother-to-infant HIV transmission. Due to its low cost and ease of administration, this regimen could have a significant impact on reducing perinatal transmission of HIV globally.
Programmatic Update: Dr. Killen reviewed the timetables of the HIV Vaccine and HIV Prevention Trials Networks. NIAID expects to award grants to the leadership cores by the end of the year and make awards to the clinical sites by next June.
Miscellaneous: Dr. Killen updated the committee on several topics that had been discussed at past meetings and reviewed the Institute's progress in developing a 2- to 5-year strategic plan, which is part of an NIH-wide effort to communicate research goals and obtain public input during the priority-setting process. He explained that the Institute is continuing to investigate possibilities with respect to tissue banking and will hold a meeting early in the year 2000 as the next step in exploring the different options available.
Dr. Killen called the committee's attention to a report on proposed changes for NIH's Center for Scientific Review, which is currently available on the Web for public comment. Dr. Nathanson briefly touched on how the changes proposed would affect the AIDS Initial Review Group (IRG).
Dr. Killen concluded his remarks by thanking departing members, Drs. Ellner, Pitha-Rowe and Tarpley for their valuable service on the ARAC.
Update from Program Reviews: Dr. Neal Nathanson
Dr. Nathanson, Director of the Office of AIDS Research (OAR), updated the committee on the results of two external reviews that were held - one of the NIH's Pediatric AIDS Research Program and one of Centers for AIDS Research.
Pediatric Research Program: Dr. Nathanson reviewed the trends in perinatal AIDS transmission, which is disappearing in the U.S. but remains a problem in the developing world, particularly in sub-Saharan Africa. In order to effectively discuss the global epidemic and the future direction of NIH's pediatric AIDS research program, the review panel was divided into three groups: children under 2 years of age, those between 2 to 13 years of age, and those between 13 and 21 years of age. The needs of and scientific issues for each of these groups differs with respect to therapy and prevention, both in the U.S. and internationally and each panel outlined what they felt were the most pressing scientific questions. Dr. Nathanson stated his hope that the final report would move to a statement of priorities within the three major areas.
Centers for AIDS Research (CFAR): The final report from the CFAR program has been issued and the review panel commended the program on its success. The panel made a number of recommendations including, the following: 1) increase the budget over the next 3 years and extend all awards to 5 years, while maintaining the present number of awards and the annual competition for these awards; 2) make no administrative reductions; and 3) supply 1-year bridge grants to centers whose grants are not renewed to enable these groups to reapply. The review panel also suggested that NIH establish "developmental awards" for qualified institutions that are too small to qualify for a full-size grant. Dr. Nathanson discussed the OAR's proposed responses with the ARAC, and indicated that these would also be discussed at the upcoming OAR Advisory Committee meeting. During discussion, it was noted that the review panel also emphasized the need to hold the individual centers accountable for their work and progress. Outcomes specific to the CFARs have to be measured.
Update on Long-Term Effectiveness Research: Dr. William Duncan
Dr. Killen opened this part of the discussion by updating the committee on the RFA for the Adult AIDS Therapeutics Clinical Trials. He noted that during the initial review process, the reviewers stated that most of the 6 major areas of research identified in the RFA had been adequately addressed by one or more of the applicants. However, the area of prospective, long-term effectiveness research was not addressed in toto by the applicants. The reviewers agreed that such research is an essential component of a comprehensive research program, and is needed to optimize the use of new therapies and to translate clinical research into clinical practice.
Initially, NIAID planned to issue a new RFA focused on long-term effectiveness research. However, given the specific concerns of the initial review, widespread misunderstanding of NIAID's intentions, and the complexity and uncertainty of the scientific methodology needed to carry out this type of research, Dr. Killen said that it would be more prudent to gather additional information and advice before proceeding. Toward that end, NIAID will organize one or more workshops to better define the scientific questions and research approaches needed to address them. NIAID will also meet with the leadership of the applicant organizations to explore all of the available options for response to the reviews since there were significant scientific and/or operational concerns with some of the applicant groups. He asked the committee to focus their discussion on what is needed in long-term effectiveness research and how such research might best be accomplished. This will help as NIAID proceeds to develop its scientific plans.
Dr. Duncan presented some of the scientific issues involved with this research, how NIH sees long-term effectiveness fitting into the overall AIDS therapeutic research agenda, and how NIH defines the key research questions. Dr. Duncan said the ultimate goal of this research is to support the development of treatment guidelines for HIV-AIDS at all stages. Present guidelines are based on short-term studies and the natural history cohort studies. However, long-term data is needed. He listed six key questions that need to be answered, including the long-term effect of therapeutic regimens on clinical outcome and the need for methodological research that will guide the development of trials. We need to determine the optimal use and timing of when to introduce therapeutic modalities from early infection through advanced disease, when to start therapy, when to change it, and how to treat patients who fail to achieve viral control on their first regimens.
During discussion, one committee member said the methodological needs should have the highest priority. Because of the fragmented nature of the U.S. health-care system, it will be extremely difficult to get the population most affected by HIV/AIDS into long-term clinical trials. In trying to clarify what is meant by "long-term," Dr. Duncan indicated that such trials could take from 5 to 10 years depending on the specific research question. Another committee member noted that AIDS is now becoming more of a chronic illness and more expertise on chronic disease is needed to shape an initiative dealing with long-term issues. It was suggested that NIAID seek advice from experts in other fields, such as oncology and cardiovascular disease, who may be able to provide models that would shed light on approaches to HIV disease. Creative methodologies, such as case control studies, may be less time consuming and less expensive than controlled clinical trials.
Public Comment Period. Five people spoke for 5 minutes each during the public comment period. Mr. Harrington, Mr. Kuromiya, and Mr. Fortenberry also provided written statements.
- Mark Harrington, Treatment Action Group (TAG) spoke in favor of rigorous, randomized, controlled trials. He noted that useful points from the committee discussions were not included in the RFA, particularly language and evaluation criteria supportive of groups with a public health science focus and the call for adequate numbers of public health experts on the review panel. In his view two networks thus scored poorly because the reviewers did not understand the public health aspects of their proposals. He pointed out that the current RFA does not adequately address co-morbidity and co-infections. He noted substantive concerns with some of the applicant organizations. He told the committee that some of the best scientists in the networks involved have threatened to leave or withdraw if they are subjected to another round of recompetition and urged NIAID to find an alternative approach. He asked NIAID to work with the current applicants, double the funding for this area of research, and make awards, hopefully by January. He also suggested that NIAID hire a senior individual to facilitate Phase IV trials.
- Ryland Roane, CPCRA Community Constituency Group, summarized CPCRA's experience with long-term clinical trials. He felt that funding for the long-term effectiveness research at the level noted in the RFA that was withdrawn is not adequate. He asked for the opportunity to negotiate CPCRA's current application and urged NIAID to fund these projects soon.
- Kiyoshi Kuromiya, Critical Path AIDS Project, recommended conducting long-term trials where people get their primary care and spoke against delaying the trials.
- Rich Fortenberry, Ryan White Title II Community AIDS National Network, stressed the importance of studying the longitudinal effects of treatment regimens on a population that is living longer.
- Brian Mahoney, WRAP-CAB, advocated continuity and asked that research not be halted while the scientific agenda is further refined. He favored flexible networks that can meet changing scientific agendas and standards of care.
In the ensuing discussion, Dr. Killen emphasized that currently funded research programs will not be interrupted as a result of this assessment process. None of the ongoing clinical trials or the accrual of new subjects into them will be halted. One committee member noted that he hadn't seen so much public response to any issue and hoped NIH saw this response as a major demonstration. Dr. Killen said that NIAID would hold one or more workshops or "think tanks," and would include researchers beyond the fields of AIDS and even infectious diseases. The purpose of these think tanks would be to define the scientific agenda for this type of research and identify the best methodological approaches. DAIDS will bring the information back to the Council and the ARAC at the next meeting for further discussion and for a decision as to how to proceed.
Concept Review: Clinical Trials Operations and Monitoring Contract - Dr. J. Flores
This 5-year, $1.5 M contract will provide DAIDS-supported prevention and therapeutic clinical trials with operational and training support, as well as monitoring for compliance with Federal regulations and NIAID policies. Dr. Flores explained why the contract is needed, who will be supported, and the nature of the services covered.
Dr. Neutra summarized the committee's views that the RFP should include language that delineates the types of expertise and personnel that would need to be available on the contract, and that when working with international sites, close attention should be given to different standards of monitoring and ethical considerations. The concept was approved with the modifications Dr. Neutra specified.
Concept Review: Collaborations for Advanced Strategies in Opportunistic Infections and HIV-Associated Complications - Dr. M. Power
This concept renews a $1.5 M program announcement to encourage and support multidisciplinary research projects that could lead directly to advances in the clinical management of complications related to HIV, particularly Hepatitis C and metabolic dysregulation.
The committee discussed the title of this concept, with some saying it should be more specific and others preferring the flexibility of its broad title. The committee voted to approve the concept.
Concept Review: Non-human Primate Models of AIDS for Evaluating Therapies - Dr. R. Black
This 7-year initiative would renew contracts for in vivo testing in non-human primates. Specifically, the contract, which will cost $3.3 M in its first year, will provide for proof-of-concept and efficacy evaluation of prevention and therapeutic strategies. Dr. Black reviewed the accomplishments of the ongoing studies with respect to topical microbicides and treatment strategies, talked about the role of non-human primate models in drug evaluation, described how investigators will be able to access these resources, and summarized the review criteria that will be used.
During discussion, one committee member urged that this concept be cosponsored by the National Center for Research Resources (NCRR). The committee voted to approve the concept.
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