7. Report of the Joint Meeting of the AIDS Subcommittee, NAAIDC, and the AIDS Research Advisory Committee

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. Killen

Dr. Killen briefed the committee on the FY 1999 budget and President’s 21^st Century Research Fund, which provides a $1.15 billion increase in funding for NIH in FY 1999, and increases NIH funding by more than 50% over the next five years. NIAID will receive $1.47 billion, an 8.6% increase over FY 1998. The bulk of these funds (66.6%) will continue to be devoted to Research Project Grants.

Dr. Killen then reviewed a meeting he attended on the ethical aspects of conducting HIV vaccine trials in developing countries. The meeting was organized by UNAIDS, and co-chaired by NIAID and CDC. It was intended to gather information in preparation for an upcoming UNAIDS-sponsored meeting to be conducted in Geneva, Switzerland (June, 1998). The goals of the Geneva conference will be to develop ethical guidance for the conduct of HIV vaccine trials, and recommendations for specific modifications to the International Ethical Guidelines for Biomedical Research Involving Human Subjects, produced by the Council of International Organizations of Medical Sciences (CIOMS Guidelines).

Dr. Killen also discussed the results of a perinatal transmission trial conducted by the CDC in Thailand. The trial evaluated the use of short-course ZDV given to HIV-infected women during the last 3-4 weeks of pregnancy, and during labor. Findings were significantly in favor of the ZDV arm. Based on these data, a joint statement was issued by UNAIDS, CDC and the NIH, recommending the discontinuation of the placebo arm and/or substitution of the ZDV regimen in current trials in developing countries. A series of conferences was also launched in Geneva to determine how these recommendations will be implemented in developing countries.

May 18^th, 1998 marked the first anniversary of President Clinton’s challenge to the scientific community to develop an HIV vaccine by the year 2000. The AIDS Vaccine Advocacy Coalition (AVAC) issued their second annual report card on the status of HIV vaccine research. Overall, the report reflected positively on NIAID’s progress and offered constructive suggestions for improvement. To date, NIAID has evaluated 23 vaccine candidates and 10 different adjuvants in 49 phase I/II clinical trials in over 2900 volunteers using 10 routes of administration.

Dr. Killen noted that he expects to fill the position of Associate Director for the Vaccine and Prevention Program shortly. Dr. Neal Nathanson was welcomed as Director of the Office of AIDS Research (OAR), and Dr. Cladd Stevens, outgoing ARAC member, was thanked for her participation.

Concept Review: Adult Therapeutics Clinical Trials Program for AIDS – Drs. Duncan and Batzold

Dr. Duncan reviewed many of the accomplishments of two therapeutics clinical trials programs (Adult AIDS Clinical Trials Group (AACTG) and the Community Programs for Clinical Research on AIDS (CPCRA). Dr. Batzold outlined the critical research questions that will need to be addressed over the next several years and proposed a new structure for the competitive renewal of the adult clinical trials therapeutics program. One of the key features of the solicitation is that NIAID will request all applicants to submit an integrated package of applications, which includes a research agenda, a management plan and all of the proposed components (i.e., the sites and statistical center). A group of researchers/sites may apply to address a broad part of the research agenda or a smaller portion of it.

A group leader would assemble a team of investigators and together they will define their research focus. The team will then identify a statistical center, clinical sites, laboratories and operations centers. This group would then put together a comprehensive research agenda, which would be presented in a core application along with a management plan. The clinical sites and statistical center would still prepare individual applications, but all applications will be submitted simultaneously. Dr. Batzold went on to describe the peer review process, the oversight of the program and a timeline with an anticipated award date of January 2000.

The committee heard the reviews of Mr. Delaney, Drs. Ellner and Tarpley [in absentia] and then discussed the concept at considerable length. Following the discussion, the committee gave concept approval to this initiative with the following modifications:

1. A Therapeutics Advisory Committee should be established as a subcommittee of the ARAC, with additional representatives as needed. The committee would advise NIAID and the NIH on overall research priorities and direction in HIV therapeutics, and on the integration and coordination of the clinical research networks.
2. The RFA should encourage applications from more than one large group and clearly state that the total available funds will not be awarded to a single group.
3. The RFA and review process should allow for applications from individual sites independent of those identified by the group leadership.
4. The RFA should include language and evaluation criteria that are supportive of groups with a "developmental" science orientation as well as those with more of a "public health" science focus.
5. The RFA should be explicit that no barriers to institutional participation in more than one group exists nor should they be imposed as criteria for group membership.
6. The RFA must be explicit that incumbency is not a prerequisite to application and must contain evaluation criteria that clearly states how new entrants and incumbents will be evaluated.
7. In order to ensure rigorous and outstanding peer review, relaxation of conflict of interest rules for the initial review group should be sought.
8. The peer review group must contain adequate numbers of experts in the public health aspects of the stated scientific agenda reflective of its increasing importance.

Overview – HIV Vaccine and Prevention Research Program – Dr. Killen

Dr. Killen presented an overview of NIAID’s vaccine and prevention trials networks (AIDS Vaccine Evaluation Group (AVEG) and HIV Network for Prevention Trials (HIVNET). He also reviewed the strengths and weaknesses of the current system and then discussed the advantages of creating two separate networks – one for vaccine research and one for other prevention research. The creation of two networks would allow NIAID to integrate clinical vaccine science into a multi-disciplinary, globally oriented research and development program. It would also emphasize NIAID’s commitment to and strengthen the prevention research program.

Concept Review: HIV/AIDS Vaccine Trials Network (HVTN) – Dr. Heilman

Dr. Heilman presented the concept for the initiative to establish an HIV/AIDS Vaccine Trials Network (HVTN) in order to unify and expand the domestic and international efforts of the current AVEG and HIVNET vaccine trials groups. She discussed the goals, objectives and plans for the HTVN, which would include one network consisting of 6 - 10 clinical sites, a central data center, and a coordinating center. The fundamental needs of the vaccine network would include the ability to: 1) at least, maintain or increase NIAID’s capability of doing Phase I and Phase II evaluations of new vaccines; 2) ensure the ability to address fundamental research questions at the basic-clinical interface; 3) move rapidly and quickly into large trial design.

The network would be formed by a core of researchers who can address a broad range of needs; together they would develop a research agenda that can address the three areas that have been identified. The agenda would undergo peer review; the laboratories, statistical center and clinical sites would be identified as part of the overall research network, and would undergo peer review separately.

The committee heard from Drs. Letvin and McIntosh, and Ms. Williamson, who reviewed the concept. Committee members then raised and discussed many questions regarding the nature and size of the various sites, possible inclusion of small scale basic research using limited numbers of people, and the need for ongoing collaborative efforts between the vaccine and prevention networks.

The committee voted to endorse the concept of creating an integrated multi-center network of clinical vaccine science, and requested that the following principles be incorporated into the RFA:

1. The leadership of this effort would consist of individuals with the broad range of scientific and community expertise needed to carry out the scientific agenda, and would be drawn from the institutions where the agenda would be carried out, and NIAID staff. The leadership would have responsibility for developing and implementing the scientific agenda and thereby determining the expenditure of funding for the overall vaccine research effort.
2. The vaccine and prevention research networks should work closely together, sharing expertise and resources. They should also collaborate with others when appropriate.
3. Individual institutions might be part of the vaccine network or both the vaccine and prevention networks.
4. A smooth transition from the current to the future system should be carefully planned. There should be seamless continuity of ongoing studies, and new studies should not be delayed.

Concept Review: HIV/AIDS Prevention Trials Networks (HPTN) – Dr. Fowler

Dr. Fowler described the concept for the HIV/AIDS Prevention Trials Network (HPTN) initiative. The overall goals of the HPTN are to develop and test a broad range of innovative, biomedical and behavioral interventions, to reduce HIV transmission among high-risk populations, both in the U.S. and worldwide. The proposed network would be an evolution of the prevention activities that are already underway or planned in the current HIVNET, but it would be better positioned to focus on the critical scientific needs and address many of the existing gaps in our understanding of prevention approaches.

The proposed structure would include a core leadership developing a research agenda, clinical sites, a statistical center and laboratory. The major areas of focus of the network would include new efficacy trials, particularly those involving promising new microbicides, perinatal approaches, behavioral and barrier approaches, STD treatment and other new ideas. It would conduct Phase I and II studies to address safety and toxicity issues that would be important for Phase III studies, and as part of that, nest basic laboratory studies. The network would continue and build upon the collaborative relationships that have been established by the HIVNET, e.g., with the acute infection network, pediatric AIDS Clinical Trials Group and international organizations. It would also work closely with the vaccine network on future collaborative studies.

The committee heard the comments of Drs. Deyton (in absentia), Jaffe (in absentia), and Ms. Williamson, who reviewed the concept. Discussion centered on possible loss of the scientific expertise and community connections that currently exist within the HIVNET as well as the AVEG, distribution of funds between the two networks; and various aspects of coordination and implementation.

The committee voted to endorse the concept of strengthening the overall prevention science effort, and requested that the following principles be incorporated into the RFA:

1. The vaccine and prevention trials networks should work closely with each other, sharing expertise and resources. They should also collaborate with others when appropriate.
2. The leadership of this effort would consist of individuals with the broad range of scientific and community expertise needed to carry out the scientific agenda, and would be drawn from the institutions where the agenda would be carried out and NIAID staff. The leadership would have responsibility for developing and implementing the scientific agenda and thereby determining the expenditure of funding for the overall prevention research effort.
3. Individual institutions might be part of the prevention network, or both the vaccine and prevention networks.
4. A smooth transition from the current to the future system should be carefully planned to ensure continuity of ongoing studies.

Concept Review: Clinical Site Monitoring Project – Dr. Duncan

Dr. Duncan presented the concept for the renewal of the clinical site monitoring initiative, which monitors all clinical studies conducted in the adult and pediatric ACTG and the CPCRA. The contract is ongoing through FY 2000, has a five-year duration, and represents 4% of the total DAIDS budget for treatment trials. The first year cost of $5.6 million will cover the increased costs of monitoring foreign sites. The committee heard from Drs. Stevens and Lehrman, who reviewed the concept. The committee approved the concept for this initiative.