Ed Tramont, M.D., Director, DAIDS
Dr. Tramont welcomed the committee and introduced four new members: Drs. Susan Buchbinder, Jeffrey Lennox, David Margolis, and Janet Collins who will be replacing Dr. Jaffe in an ex-officio capacity, and was introduced although she was not able to be at this meeting.
Dr. Tramont reported that Congress is still working on the FY2005 budget and that NIAID funding would rise from $4.3 billion in FY2004 to $4.4 billion (House bill) or $4.56 billion (Senate bill), an increase of 2.3-3.6 percent. This includes increases in AIDS, non-AIDS and biodefense research. By comparison, the overall NIH budget would increase from $27.8 billion to $28.5 or $30.0 billion, an increase of 2.5-3.7 percent.
Dr. Tramont reported that the recompetition of the DAIDS clinical research networks is moving forward on schedule. The solicitation for leadership groups should be released by early November with proposals due in spring 2005; it is anticipated that the solicitation for sites will be in early 2005, with proposals due in fall 2005. Awards for both solicitations will be made in the early 2006. Progress is also being made on the virtual vaccine research center, a component of the Global HIV Vaccine Enterprise that was approved by ARAC during its recent teleconference. Thus far, a coordinating committee of the Enterprise has been established and five scientific priorities have been identified for the center: envelope vaccine design, T-cell vaccine design, lab centralization, development and manufacturing of constructs, and correlates of immune protection. NIAID’s initial contribution to this initiative will be the Center for HIV/AIDS Vaccine Immunology (CHAVI), for which an RFA will soon be issued. An article on CHAVI appeared recently in Science and ARAC’s approval of the CHAVI concept was a vital step in launching this initiative.
Update from AIDS Vaccine Research Working Group
Dr. Bradac, Chief, Preclinical Research and Development Branch, NIAID, and Executive Secretary, AIDS Vaccine Research Working Group (AVRWG), reported that the AVRWG – whose 14 members serve three-year rotating terms – held three meetings in 2004 at which it addressed a wide range of topics, including: status of HIV vaccine development (AVRWG’s summary and recommendations are posted on the DAIDS Web site); DAIDS solicited programs (AVRWG recommended that DAIDS target program announcements less narrowly, do more to recruit and educate reviewers, and get more innovative approaches into the pipeline); guidelines for moving candidates from Phase 1 to 2 to 3 in the HIV Vaccine Trials Network (AVRWG suggested that the acceptable threshold will and should rise over time); RV144 trial in Thailand (four AVRWG members reviewed this trial in progress and agreed that the sponsors should [1] elevate viral load to co-primary objective along with acquisition, [2] send immunogenicity data to the DSMB in real time for a sub-cohort of 300 vaccine and 100 controls, and [3] instruct the DSMB to consider stopping the trial for operational futility (poor enrollment), but not conduct a futility analysis at this time); and EuroVacc (AVRWG recommended that DAIDS support this consortium of 34 laboratories in 8 nations, which asked for assistance in manufacturing, safety and toxicity testing for Phase 2 trials and IND applications in the United States).
The next meeting of the AVRWG, in January 2005, will include a one-day workshop on bacterial and viral vectors. Additional meetings will be held in May and in conjunction with the AIDS Vaccine 2005 meeting in Montreal.
In response to a question from an ARAC member regarding the role of AVWRG in relation to ARAC, Dr. Bradac explained that ARAC advises DAIDS from a broader perspective and plays a special role in initiative development, whereas AVRWG gives narrower, science- and technology-based advice on relatively high-risk research questions. AVRWG’s priorities over the next year are to encourage and improve multiple vaccines on several different platforms, in order to move something forward to clinical trials. DAIDS has decided to test the EuroVacc MAV candidate.
Concept Review
Centers for AIDS Research -- Dr. Carl Dieffenbach
The Centers for AIDS Research (CFAR) is a multi-institute initiative to encourage multidisciplinary, collaborative research on AIDS prevention, detection and treatment. Established in 1988 and renewed four times since then, CFAR uses the P30 (centers grant) mechanism to support 18 centers and 2 developmental centers with a total budget of $29.4 million in FY2004, or 1.1 percent of the NIH AIDS budget. Changes introduced in 2003 gave the program greater flexibility in funding and competitive supplements have also jump-started research in a number of high-priority, understudied areas. As a result, the CFARs have been successful in encouraging the formation of integrated, multidisciplinary research programs, often international in scope. Considering these results and the fact that 73 percent of NIAID AIDS research is conducted at CFAR institutions, the ARAC reviewers for this concept wondered if the CFAR is under funded. They suggested that one way to maintain the program’s momentum would be to conduct an external review to assess the scope and budget of the CFAR prior to the scheduled release of a Program Announcement for its renewal in 2007.
Several ARAC members reported that the CFARs provide a valuable catalyst for interdisciplinary and interdepartmental research at their own institutions, particularly in recruiting new faculty and encouraging translational research that might not have occurred without this stimulus. This program also creates expertise and infrastructure that can be used for other forms of research. The institution-based approach seems to be important, but multi-institution CFARs have proven more difficult to launch and maintain. Bigger institutions may have a competitive advantage, but the tiered structure of the grants allows for tiered measures of success; current guidelines call for the creation of one Developmental CFAR each year. One current weakness in the program is the lack of stable funding for supplemental awards, which vary greatly from year to year. ARAC reviewers suggested having NIAID (rather than NIH) issue a program announcement for supplements on an annual basis, creating an administrative shell that would simplify processing and review, even if it would not guarantee that these funds would be available every year.
Following discussion, ARAC members voted unanimously to (1) continue the CFAR program for another year with a budget of $4.5 million, with a full-scale program review to follow prior to the scheduled release of the PA for renewal in 2007; (2) ask the CFAR Steering Committee to create a shell mechanism to administer supplemental funds on an annual basis.
Integrated Preclinical-Clinical Research Program – Dr. Carl Dieffenbach
The Integrated Preclinical-Clinical Program (IPCP) was launched in 1997 to move novel HIV therapies from the bench to the clinic. The new program announcement would list a number of excluded research areas, in order to avoid funding areas where research is already underway, and it expands the term of the grants from four years to five, while limiting the number of renewals to one. Private sector involvement is required to ensure progress; when this requirement was suspended, no products moved into clinical trials. Review by ARAC members was supportive. ARAC voted unanimously to renew the program as modified.
TB Drug Discovery and Development Teams – Dr. Sandra Lehrman
This is a new initiative to create Tuberculosis Drug Discovery and Development Teams, using the N01 mechanism to advance promising drug candidates to Phase 1 and increase the number of candidates in clinical trials. The initiative would fund one or two consortia of university and industry researchers using the N01 (cost-reimbursement) mechanism. ARAC reviewers thought that this combination of expertise would be effective and that cost-sharing was the appropriate financial approach. During discussion ARAC members raised questions about intellectual property arrangements and the need to deliver the resulting drugs to impoverished patients; these arrangements will be negotiated in advance, often with pricing details. ARAC voted unanimously to approve the proposed initiative.
Development of Drugs for Co-Infections in AIDS – Dr. Sandra Lehrman
This is a renewal of an existing program, with modifications, for an additional seven years. Five R&D contracts are already being funded; five new contracts would be awarded, with first-year costs of $3.5 million. Existing activities are designed to acquire, screen and assay potential therapeutics and advance them toward clinical development; the proposed modification would expand the program from TB to other co-infections (e.g., PCP, enteric parasites, herpes viruses, HCV, and emerging diseases). ARAC reviewers indicated that this was an important program that should be expanded, but they called for measures to ensure the accessibility and affordability of products for developing countries. The program will include an external panel for setting priorities and reviewing progress, and technology will be transferred to both private and public entities for development and marketing. Both diagnostics and therapeutics will be included. In discussion, ARAC members indicated that the need for these types of therapeutics has never gone away, and that opportunistic infections are common in the inner city as well as the developing world. ARAC voted unanimously to approve the proposed extension.
Immunology Quality Assessment (IQA) Program -- Dr. Sandra Lehrman
This concept proposes the renewal and expansion of the IQA program, which provides for standardization and proficiency testing in immunological tests done at NIAID-supported libraries, as well as facilitating the adaptation and validation of new assays for use in multi-site clinical studies. The program also serves as a central facility for storage and distribution of reagents. This program has already provided vital support for AACTG and PACTG studies, and future efforts will address the need for proficiency training and standardization of statistical standards in international studies. The IQA uses the N01 (contract) mechanism, and the proposed seven-year extension would have first-year costs of $2 million and total costs of $15 million. ARAC members noted that this activity will be particularly important for sites in resource-poor areas; consequently, when resources are limited the priority should go to training, assays and data quality that are important to large international trials. CD4 assays, in particular, are becoming an issue at international sites. ARAC approved the initiative and approved the proposed extension and expansion of this program.
NIAID Specimen Repository -- Dr. Sandra Lehrman
This concept is for the renewal and expansion of a contract that maintains a centralized repository that receives, catalogs, stores, retrieves, and aliquots specimens collected from subjects in domestic and international clinical studies sponsored by NIAID. As of June 2004, the repository already held 3.87 million specimens from current and completed studies, and a total of 6 million specimens are projected by 2008. The current emphasis is on planning and quality control, as well as increasing awareness of and access to the specimens by interested researchers. Future priorities include evaluation of new technologies for specimen storage, as well as QA for specimen viability. ARAC reviewers called for easier access to specimens, greater standardization, and web-based data on holdings and utilization.
In discussion it was noted that less than 1 percent of specimens are ever touched after the protocol ends and the research papers are published. The question was raised as to whether it is reasonable to develop a scheme for purging specimens after a certain period. No reasonable proposal for a time limit was proposed. The adult ACTG, which maintains its own repository, has decided to optimize and streamline its own collection and it was suggested that NIAID develop a rationale for both collecting and maintaining specimens, or develop an algorithm that empowers investigators to do more with less. It was also noted that foreign patients and governments often object to transferring specimens to U.S. repositories, and this may become a bigger problem with the growth of international studies. There was agreement that NIAID should do more to promote the access to and use of existing specimens, particularly among researchers who are not part of the networks. At the end of the discussion, ARAC approved the extension and expansion of this program.
Simian Vaccine Evaluation Units – Dr. Jim Bradac
This concept proposes the renewal of an N01 contract, which provides nonhuman primates, facilities and staff to evaluate candidate SIV and HIV vaccines. Existing units have supported 95 protocols since 1991, including 60 vaccine immunogenicity and efficacy studies conducted at the SVEUs. The resulting virus challenge stocks have been put into the shared reagent programs. ARAC reviewers generally approved of the program, although they also called for the development of a more “human-like” challenge. The proposal calls for a seven-year extension with first-year costs of $9.5 million and overall costs of $40 million.
In the discussion that followed, ARAC members said that despite some concordance between human and nonhuman immune responses, further comparative studies are needed to understand the degree of correlation. Care is needed to maximize the use of primates relative to the overall HIV research effort – that is, to ensure that primate data are relevant to humans, and that primates are used only to answer questions that can’t be answered in humans (or mice.) Following this discussion, ARAC voted unanimously to approve the initiative.
Reorganization of the Panel on Clinical Practices for the Treatment of HIV Infection -- Dr. Sandra Lehrman
Dr. Lehrman reported that the departmental panel that develops the guidelines for treatment of HIV-AIDS has in the past been coordinated by the Office of the Director, NIAID. It was suggested that the panel become a working group of ARAC to give it a formal home within the NIH. The question is whether ARAC would be interested in housing the panel. Staff can develop a report for consideration at the January 2005 meeting, addressing such questions as charter, membership, and support.
Dr. Alice Pau, Office of Clinical Research, NIAID, reported that the current panel was established in 1996 and is currently co-chaired by Drs. Cliff Lane and John Bartlett. It has 31 members, including clinicians and researchers as well as representatives from CDC, PHS, NIH, HRSA, and the Department of Veterans Affairs. It is responsible for guidelines for prescribing antivirals to adults and adolescents. Separate panels exist to develop standards for pregnant women, children and opportunistic infections. ARAC member Henry Masur, who is also a member of the panel, said that the panel would like to broaden its mandate to include other therapies and other patient groups, as well as additional relevant agencies. The panel meets annually face-to-face and monthly by conference call. Its recommendations represent the gold standard for treatment and funding decisions. There have been 12 revisions since 1997, and the Web site recorded 700,000 downloads in 2003.
Jack Whitescarver, Director, Office of AIDS Research (OAR), said that OAR has supported this panel over the years because of the need to get relevant information to caregivers, but while the panel synthesizes and updates the information, it is not a chartered committee. Dr. Masur suggested that ARAC’s role should not be to review and approve the details of the treatment guidelines, but rather to receive and endorse the guidelines developed by the panel.
Dr. Holmes asked a subcommittee to develop a report on this proposal, for consideration by ARAC in January. Members of this subcommittee: Holmes, Masur, Collins, and Whitescarver, with Lehrman and Pau to coordinate with the panel’s co chairs. Topics to be included are: plans for guideline development; role of ARAC and representatives of NIAID, NIH and HHS; partnerships with other agencies and bodies; and scope of guidelines.
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