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  1. Joint Meeting of the AIDS Subcommittee, National Advisory Allergy and Infectious Diseases Council and AIDS Research Advisory Committee

Ed Tramont, M.D., Director, DAIDS


The AIDS Research Advisory Committee (ARAC) met on Monday, January 24, 2005, from 1:00 to 5:00 p.m., at the Natcher Conference Center on the NIH campus in Bethesda MD. Members participating: Drs. Susan Buchbinder, Janet Collins (ex officio), Charles Davis, Lawrence Deyton (ex officio), Ashley Haase (OARAC liaison), King Holmes (chair), Brooks Jackson, Phyllis Kanki, Jeffrey Lennox, Dorothy Lewis, David Margolis, Rev. Ray O’Brien, Andrea Ruff, Nathan Thielman, and Jack Whitescarver (ex officio). Participating NIAID staff included: Drs. Carl Dieffenbach, Mary Fanning, Richard Hafner, Peggy Johnston, Jonathan Kagan, Sandra Lehrman, and Dr. Edmund Tramont, and Mr. Daniel Montoya and Mr. Matthew Murguia. Ms. Rona Siskind served as Executive Secretary.

Director’s Report – Edmund Tramont, MD

Dr. Tramont, Director, Division of Acquired Immunodeficiency Syndrome (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), welcomed the committee and introduced Janet Collins, acting director, Center for HIV and STD Prevention, Centers for Disease Control and Prevention as the newest member of the committee. He reported that NIAID’s budget for FY2005 will be $4.4 billion, with AIDS accounting for 33.2 percent and biodefense 37.6 percent; the budget includes $14.4 million for the Center for HIV/AIDS Vaccine Immunology (CHAVI). DAIDS expects that it will have a budget of approximately $800 million. The recompetition of the all of DAIDS HIV/AIDS Clinical Trials Networks is moving forward: the solicitation for leadership groups was released in November 2004 and the solicitation for sites will be released in February 2005. It is anticipated that grant awards will be made in early 2006. Full details are available at the Network Web site, www.niaid.nih.gov/daids/rfa/network06/.

DAIDS continues to support a broad, well-articulated portfolio of programs ranging from basic through preclinical to clinical research, aimed at protecting the uninfected, preventing disease progression, and understanding the mechanisms of HIV pathogenesis. In the aftermath of doubling the NIH budget; however, NIAID will face challenges in continuing to build its programs in vaccines and biodefense. Future concerns for DAIDS include post-study needs of clinical trial participants, collaborations with other NIH institutes, and improving the research capabilities of international partners.

Panel on Clinical Practices for the Treatment of HIV – Cliff Lane, MD, and John Bartlett, MD

Drs. John Bartlett and Cliff Lane, co-chairs of the Panel on Clinical Practices for Treatment of HIV Infection, were present to discuss the proposal to make the panel a working group of ARAC. Convened by DHHS and the Kaiser Foundation in 1996, the panel’s 37 members published the first guidelines for adult and adolescent treatment in April 1998. Since then they have held monthly conference calls and annual meetings to review current clinical data and update the guidelines as needed. To date, 14 revisions have been released. Guidelines for pediatric and perinatal care, occupational exposure prevention, post-exposure prophylaxis, and for treatment and prevention of opportunistic infections, are addressed by other panels. The Web site http://aidsinfo.nih.gov, which provides comprehensive information on HIV/AIDS treatment and prevention clinical trials and research for providers, HIV-infected individuals, and the general public, also maintains the most up-to-date version of all of these guidelines. Following each revision to the guidelines, AIDSinfo experiences a substantial increase in the number of downloads and requests.

The Panel is not currently housed within any specific agency, although NIAID has provided logistical support over the years. Drs. Bartlett and Lane believe that housing the committee within an existing NIAID advisory body would be logical and appropriate. They propose that one member of ARAC would be appointed to the panel, and that panel activities (including guideline updates) be reported/reviewed at ARAC meetings. Several ARAC members said that there was no apparent downside to this proposal, and that higher level review would give the panel’s guidelines more status and impact. However, the Advisory Committee of the NIH Office of AIDS Research is also willing to house the panel as a working group, and because that Committee advises the Secretary of DHHS and all of NIH, as well as OAR, it too serves as a logical base for the panel. The panel will be meeting in person at the upcoming CROI meeting and will discuss their options in greater detail. ARAC members unanimously expressed enthusiastic acceptance of the proposal to make the panel a working group of the ARAC, should the panel decide to proceed in that direction.

International Database for Evaluation of AIDS – Carl Dieffenbach, Ph.D.

Carl Dieffenbach, Director, Basic Sciences Program, DAIDS, presented the concept of an International Database for Evaluation of AIDS (IDEA), which grew out of a workshop held in September 2004. Many of the unanswered questions about the AIDS epidemic – impact of prevention and therapy at the population-level, in diverse patient populations and over the long term, as well as the population prevalence of drug-resistant strains – can be addressed only with large international data sets, using “harmonized” definitions and data, and including data from appropriate control and at-risk populations. The feasibility of creating such databases has been demonstrated in DAIDS cohort studies, Department of Veterans Affairs medical records, and several European HIV databases. DAIDS proposes to establish a network of globally distributed data centers to compile data, harmonize data across regions, and determine critical research questions that can be studied with this meta-database. The network’s activities would be supported through a cooperative agreement (U01 mechanism) at a cost of $5 million for the first of five years.

In the discussion that followed, ARAC members agreed that this was a reasonable approach and much needed, but suggested that DAIDS and potential applicants seek input from other existing organizations that are developing large international databases (e.g., CDC-GAP, WHO). Most members agreed that geography was the logical organizing principal and would facilitate the identification of a control group in each region. Regional centers would be encouraged to self-identify areas of interest or expertise, such as prevention, transmission, treatment, or sub-populations. However, it was suggested that DAIDS might want to consider in a second round that proposals be sought based on science rather than geography. Data should be gathered from all sources, not just clinical trials. Selecting regional database centers would facilitate selection of appropriate control groups, relevant to the areas of interest and populations studied. ARAC members also stressed the need for ensuring high quality data input, regardless of source, and saw this as a way to both make better use of existing data and make all data better in the future.

Following discussion, ARAC members unanimously approved the concept for this initiative.

Vaccine Research Program -- Peggy Johnston, Ph.D.

Peggy Johnston, Director, Vaccine Research Program, DAIDS reported that NIAID’s goal remains one of finding a vaccine that works, at least partially, and then improving its design so that it will work better, in all people, against all viruses and routes of transmission, for a long time. A number of scientific and programmatic advances occurred in 2004. Several new vaccine candidates have advanced to Phase I trials, planning is underway for two Phase IIB trials of adenovirus vector-based polyvalent vaccines, and NIAID released the RFA for a CHAVI in September. NIAID is also participating in the Global HIV Vaccine Enterprise, an international consortium designed to increase coordination among vaccine development efforts worldwide.

Scientific challenges remain the most significant rate-limiting factors in HIV vaccine development. In 2005, the most important scientific challenges are (1) eliciting broadly neutralizing antibodies, (2) inducing cellular immune responses capable of preventing HIV escape, (3) exploring novel approaches such as obtaining more durable immune responses and mucosal responses, and (4) advancing the most promising candidates into efficacy trials. To address these challenges, Dr. Johnston presented for review and approval the concepts for three new or continuing components in the NIAID Vaccine Research Program:

  1. The Innovation Grant Program, which has awarded 268 R21 grants since 1997, addressing a wide range of scientific questions in HIV vaccine design, development and testing. NIAID seeks to renew the program for another two years, with a first-year cost of $5 million for 20 awards. ARAC members indicated that this program has proven itself to be an important mechanism for attracting new ideas and encouraging investigators to undertake high-risk research. Many recipients have gone on to become PIs or key collaborators in more advanced vaccine R&D activities. The committee unanimously approved the concept for this initiative.

     

  2. HIV Vaccine Design and Development Teams, an existing program aimed at supporting consortia of academic and industrial scientists who can take promising preventive vaccine concepts into testing in humans. The mechanism has been a Broad Agency Announcement leading to a contract in which the statement of work is developed by the offeror, with strong oversight and strict audits by NIAID. The first three rounds of this program yielded 29 proposals, of which 9 were funded; the first 4 teams to be funded have already moved products into Phase 1 trials. NIAID is now asking for permission to continue the program for another 5 years, using the N01 mechanism and expanding the scope to include both preventive and therapeutic vaccines. First year costs would be $15.2 million for five awards. ARAC members recognized the past success of the program and agreed with plans to conduct site audits sooner. The ARAC committee unanimously approved the concept for this initiative.

     

  3. The HIV Vaccine Trial Statistical and Data Management Center, a new concept for a data hub and statistical support center for clinical trials that are conducted outside the HIV Vaccine Trial Network. The goal is to provide quality assurance/control for non-network sites, and a central place to compare data across trials. The center would be supported for 7 years using the N01 mechanism, with a first-year cost of $3 million for one center. Reviewers suggested that it would be important to get early input and buy-in from investigators; one way to do this would be to assure them that the center would stress analysis as well as QA/QC, and that the center would provide technical assistance to non-network sites. Following discussion, the committee unanimously approved the concept for this initiative.

External Scientific Review – Jonathan Kagan, Ph.D.

When the concepts for Leadership for HIV/AIDS Clinical Trials Networks and Units for HIV/AIDS Clinical Trials Networks were approved, ARAC recommended that 1) high-priority science should drive each network’s research activities and 2) each network should undergo regular external scientific review of its priorities and progress. Thus, the objectives of the external scientific review function would be to evaluate the networks’ progress in addressing their most critical scientific priorities, and advise the Networks on their plans for high-resource, high-impact clinical trials. The latter would not necessarily be addressed by the same External Scientific Reviews that would evaluate scientific progress and will be discussed separately.

Dr. Kagan, Deputy Director, DAIDS asked for the committee’s input on how these external reviews should be organized and conducted. He identified several areas that need consideration, including: what scientific areas should be represented on the External Review Group, the frequency with which a Network should be reviewed, what data should be reviewed, and what form should the report take? In addition, the role of ARAC should be considered in terms of setting an agenda, and/or membership. The outputs that would be taken into account during an evaluation such as number of patients, costs, and licensed products should also be discussed.

In the discussion that followed, ARAC members suggested that the reviews should be both strategic and operational — addressing not only whether the network is pursuing the highest priorities, but also whether it is using resources efficiently. The goal should be to do more by doing it more efficiently and effectively. Doubling the number of international sites would be progress as would the acceleration of drug development, or getting to a negative result quickly so that other research can move forward. Defining the important aspects of network operations was considered more difficult and it was agreed that having representatives from industry with expertise in operational aspects of clinical trials will be important to this process.

ARAC members Drs. Margolis and Davis and several meeting attendees offered to participate in an ad hoc group to work with Dr. Kagan to develop these ideas further and come back to the full committee for further discussion.

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Last Updated March 14, 2005