Ed Tramont, M.D., Director, DAIDS
The AIDS Subcommittee of the National Advisory Allergy and Infectious Diseases Council and the AIDS Research Advisory Committee (ARAC) met jointly on September 23, 2002 at the Natcher Building on the National Institutes of Health (NIH) campus in Bethesda, Maryland. Dr. King Holmes chaired the meeting.
Report from the Director - Dr. Tramont
Dr. Tramont introduced Dr. Holmes as the new chair of the ARAC. He welcomed Dr. Phyllis Kanki, the newest ARAC member, and announced that Dr. Brooks Jackson will serve as a liaison to Office of AIDS Research Advisory Committee (OARAC). He thanked Dr. Haynes and Ms. Saint Cyr, who are rotating off, for their services and he introduced Dr. Kevin Ryan as the new Chief of the Prevention Services Branch at DAIDS. He also described two new offices that are being created at DAIDS as part of the Office of the Director -- the Office of Clinical Research Policy & Resources and the Office of International Research.
The Strategic Planning Working Group met in March 2002 to look at the Division's research portfolio and structure. The effort has "fallen off track" because of the departure of key DAIDS staff and because Dr. Tramont needed to devote his energies to helping his wife recover from a major illness. He proposed shifting much of the strategic planning responsibility to ARAC.
Dr. Tramont briefly summarized Dr. Fauci's remarks to Council concerning HIV/AIDS related activities, including the transfer of Department of Defense HIV research efforts to DAIDS, which despite some delays, is proceeding.
AIDS Vaccine Research Working Group (AVRWG) - Dr. Haynes
Dr. Haynes explained that Dr. David Baltimore had stepped down after chairing the committee for seven years. For administrative purposes the body was transformed into a working group, with himself named as chair. He reviewed the reconstituted membership, which first met September 3-4, 2002. The scientific focus of that meeting was: Why is it so difficult to induce anti-HIV neutralizing antibodies?
Four major postulates arose:
- Neutralizing determinants are present but are not immunogenic.
- Do neutralizing antibody assays measure what is biologically relevant?
- There may be such a diversity of viral subspecies and envelope composition that it is beyond the capacity of broadly reactive neutralizing antibodies to control the virus.
- Neutralizing determinates may be expressed in too "fleeting" a manner or in too small of a space or compartment for neutralizing antibodies to gain effective access.
Two main strategies for immunogen design emerged from the meeting. One is "optimal" envelope design, with polyvalent best inducer env, using an artificial env based upon a consensus or ancestral construct. The second is a "constrained" or "triggered" approach using env-CD4 to reduce the energy requirements for antibody binding.
The AVRWG will evaluate the current vaccine pipeline to assure that resources are used well. It will review issues surrounding "superinfection" at its February 2003 meeting and is planning an international conference for September 2003.
Concept Review: Basic Sciences Program - Dr. Dieffenbach
Dr. Dieffenbach summarized the major scientific questions and focus of research:
- Therapeutic Discovery: proof of concept, new targets, moving new ideas into clinical study.
- Epidemiology: the long term natural history of ART-treated HIV disease in the US, identify factors affecting rapid and slow progression of disease, gender differences, and the impact of ART on transmission of new infections.
- Pathogenesis: what are the mechanisms of viral entry, disease progression, and viral evolution.
He reported that programmatically, the Innovation Grant Program has generated proposals for novel ideas and a broad approach for vaccines, as was intended. The major area of disappointment was microbicides.
Therapeutic Vaccine Development Resources: This is a new program of 3 years duration, with a first year cost of $2 million and an estimated 1-5 projects funded in the first year. DAIDS staff would be authorized to approve grants of up to $250,000; peer review panels would rate larger requests.
Therapeutic Vaccine Design and Development Teams: This is also a new program of 5 years duration using the N01 mechanism. Two awards would be given in the first year, totaling $2 million.
Therapeutic vaccines present challenges potentially different from preventive vaccines in that an infection is already established, perhaps with greater viral diversity and/or selection, and an already compromised host immune response. They are hoping to stimulate work in this area through support of developmental resources and design and development teams.
An important aspect of the therapeutic vaccine effort would be to build upon existing preventive vaccine standards and operating practices, and through a contract mechanism, supplement and expand production of candidate vaccines to provide enough material to use in therapeutic trials.
In review, Dr. Lewis stressed the need for close collaboration between researchers working on preventive and therapeutic vaccines because many of the concepts and measures of success or failure are the same. Dr. Jaffe questioned the need for a therapeutic program separate from preventive vaccines. Dr. Haynes said that a good preventive vaccine probably will have value as a therapeutic, but the converse may not be true. Dr. R. Johnston said the design and outcomes measured might be different, at this point we don't know enough to say. The regulatory hurdles of each also may differ.
Dr. Tramont stressed the need to standardize data collection wherever possible so that comparisons can be made between preventive and therapeutic research. Dr. Kanki said that African colleagues are particularly interested in whether preventive vaccine research might be rolled over into therapeutic trials, particularly since some of those vaccinated in preventive trials will already be infected with HIV. Dr. Kagan stressed that these initiatives will add resources to permit therapeutic research, rather than dilute funding of preventive activities and Dr. Batzold noted that people might be more willing to take risks in a therapeutic setting.
Dr. Haynes suggested that preventive work should focus on those viral isolates that are transmitted, while therapeutic work should focus on virus that has evolved under immune and drug pressures.
The committee voted to support both concepts.
Multicenter AIDS Cohort Study (MACS): Renewal and expansion is being sought for 5 years for this program under a U01 cooperative agreement, with a first year budget of $13 million. The bulk of pathogenesis work that has been supported by the MACS lab is being moved into an R01 funding stream.
Dr. Dieffenbach said that ten years ago dual NRTI therapy was coming into use and HAART was a few years down the road. The pending widespread introduction of the entry inhibitor class of drugs likely marks a similar important milestone in therapy. It is important to understand the long-term natural history of HIV in light of these therapies and the interaction of co-morbidities, which expansion of the cohort will allow. He said it was "absolutely critical from an immunological standpoint" to be able to track therapy use, changes, and compliance. It is especially crucial for understanding unanticipated toxicity.
The MACS cohort is being expanded through reenrollment, from 1,768 to 2,879 patients. Emphasis is being placed upon minority recruitment to allow for adequate powering of subset analysis. When combined with the Women's Interagency HIV Study (WIHS) the two will offer a good picture of the epidemic in the United States.
During discussion, Dr. Masur said that the MACS has provided "spectacular information, it would be a pity not to maintain this observational cohort study." The committee voted to approve the proposal.
Centers for AIDS Research (CFAR): Renewal and expansion of the program is being sought for 5 years under a P30 mechanism. The funding structure would be revised from a 2-tier to a 4-tier system that would be based upon the total dollar value of the HIV research at the center. The dollar cap at each center would double to $3 million.
The program objective is to provide infrastructure resources to support a multidisciplinary collaborative environment that promotes basic, clinical, behavioral, and translational research at the centers, under local control. The new mechanism would also allow for funding interdisciplinary program supplements and would encourage CFAR investigators and collaborating Institutions to jointly create new programs and activities. To date, there has not been this programmatic evolution and it may be that ARAC could play a role in helping to identify the types of supplements, and targeted areas that would be funded each year.
Dr. Lewis stated that the program has led to the development of R01 applications that have been more successful in passing review and getting funded. Dr. Holmes thought the program has been "a real bargain" for DAIDS. He saw greater involvement with CFARs as a way for ARAC to become more proactive and less reactive in its actions. He suggested that DAIDS formally create an interdisciplinary research program component of CFARs along the lines of what NCI has done with the Cancer Centers. The committee voted to approve renewal of the program.
Concept Review: Vaccine & Prevention Research Program - M. (Peggy) Johnston
Dr. Johnston said that the HIV Vaccine Trials Network (HVTN) has a "firm and vibrant" pipeline for vaccines. It recently initiated the first trial of a recombinant regulatory protein; has 4 other phase I trials slated to start by the end of this calendar year; 8 more candidates to enter trials in the first quarter of 2003; and 8 additional vaccines in development.
The microbicides program has candidates in phase I and II development, and a phase III study evaluating two candidates scheduled to begin in early 2003. These activities complement trials by other sponsors. A strategic plan has been developed for microbicides and will be presented at a subsequent meeting.
The EXPLORE study, which will end in late 2002, will yield the first measurement of the impact of a behavioral intervention on HIV incidence. Additional studies are looking at transmission of HIV through breast-feeding; the impact of nevirapine on transmission through breast-feeding; and the impact of antiretroviral therapy on transmission among serodiscordant couples.
Perhaps the most important unanswered question is whether any of the current vaccine or microbicide candidates offer any protection.
Building capacity and capability to conduct trials in developing countries is a key issue. This means creating the necessary research infrastructure, developing expertise for regulatory and ethical review, functional IRBs, and building political and community support, within the framework of partnership.
Innovation Grants for AIDS Vaccine Development: Renewal of this program is being sought to accelerate and sustain entry of new designs through the R21 mechanism. The first year commitment is $5 million; awards will be capped at $150,000 each, with approximate 20 grants a year made three times a year. After minimal discussion, the committee voted to support the program.
HIV Vaccine Design and Development Teams: Renewal and expansion of this program is being sought for 5 years through a N01 (milestone-driven, completion-type, cost reimbursement contract) mechanism, with a $15 million first year cost. The purpose is to advance promising concepts to the point of clinical evaluation.
Dr. Peggy Johnston said that the program helps ensure that novel approaches are funded. Applicants are required to address whether the vaccine they are developing will have to be tailored to each viral clade or whether it will stimulate immune protection across clades.
Dr. R. Johnston noted that the public is investing an enormous amount of money into this program, with a potential for the private sector to profit. Care should be taken to assure that the public interest is well served. He was comfortable with Dr. Peggy Johnston's judgment that it was premature to require detailed post-phase III commitments from grantees. The committee voted to support the program.
HIV Vaccine Advanced Development: This is a new 5-year proposal to support development from phase I into efficacy trials, through a N01 mechanism. Total first year costs will not exceed $15 million, tailored to individual needs and the quality of the applications.
The types of activities that will be supported include developing the processes for large-scale manufacturing; validating those processes; performing lot qualifications; and production of vaccine for trials. Many of these issues must be resolved prior to initiating phase III trials.
During extended discussion, Dr. Peggy Johnston said that while an academic center theoretically could carry out all of these activities, she "was not sure that we would encourage that." It is likely that an investigator would form a company to carry out some of the functions.
She hopes that by the time the program is announced, there will be "a menu of options" that the grantee will agree to in terms of their commitment for public benefit. That may include donation of vaccine to the host country, a cost-plus assurance on pricing, etc. She said they are hesitant to make an intellectual properties claim, believing that in most instances the government is not the best agent to move forward with commercial production. Also, the needs of host nations are likely to vary. The key word is flexibility, "one size will not fit all." The committee voted to support the proposal.
Microbicide Design and Development Teams: This is another new 5-year program to advance microbicides concepts into phase I trials via a focused, development-based approach, through a N01 (milestone-driven, completion-type, cost reimbursement contract) mechanism. The budget is $7.5 million for FY'03 and $10 million for FY'04. The hope is to draw industry into an area of research that medium and larger sized companies have so far avoided.
NIAID is supporting about $27 million in microbicides research, with total NIH spending of about $60 million in the field. The National Institute of Child Health and Human Development (NICHD) supports much of the additional research. NIAID is funding $250 million in vaccine research, out of the NIH total of about $400 million.
Dr. Holmes said the spin-off knowledge of the impact of microbicides on other pathogens from this program could be substantial and more broadly applicable. Dr. Peggy Johnston said a secondary goal is to develop knowledge that is applicable to other sexually transmitted diseases (STDs), in part because of the commercial considerations for such a product. The committee voted to support the proposal.
HIV Vaccine and Microbicides Preclinical Development Contract: Continuation and expansion of the current program is being sought for 4 years (with a 2 year option), at $15 million a year, through the N01 mechanism. Supported activities include preclinical and production work, product formulation, and packaging support to advance promising candidates.
Dr. Peggy Johnston said this builds upon the model used successfully with vaccine development. It would create a "virtual company" capable of carrying a compound into phase I trials. Decisions on expenditures of up to $250,000 would be made under internal review, while larger requests would be submitted to external review. She said it would give DAIDS the flexibility to contract specific tasks as needed. The Committed voted to support the proposal.
DAIDS Enterprise Information Management System - Dr. Kagan
The objective of this program is to provide DAIDS with a comprehensive enterprise-wide information system to support the scientific, administrative and regulatory management responsibilities associated with all facets of program development, implementation, oversight, and evaluation. It is the third phase of an information modernization program. It is a new 5-year program with a $5 million first year cost, implemented through a N01 contract.
The contractor who developed a similar system for the National Cancer Institute (NCI) is developing the web-based system for DAIDS, which will likely be expanded to all of NIAID.
He explained how reporting of serious adverse events (SAEs) and broad dissemination of that information on a real time basis will allow for greater patient protection, control of suspect drugs, and accountability. It will allow for quicker and easier responses to requests for information from congressional and other sources.
Some committee members feared resistance from grantees who believe their data to be proprietary. Most believe that costs are likely to escalate. The committee voted to support the proposal.
Discussion - Dr. Holmes
Dr. Holmes asked the committee if it should take a more active role in areas other than the traditional one of reviewing proposals put forward by DAIDS. That is not going to be possible in short sessions. He cited a recent article in the Harvard Business Review contrasting the features of successful and unsuccessful corporate boards, and believes that the committee does not possess one of the criteria mentioned: creating a culture where open dissent is not seen as disloyalty. He suggested that as DAIDS evolves towards taking on many pharmaceutical-business-like challenges for neglected but needed products (e.g., vaccines and microbicides) all the way through advanced product development, as proposed at the meeting, the committee may want to assume more of the responsibilities of a corporate board.
Dr. Tramont described the setting of priorities as a dynamic process where the more discussion, the better the product. He said, "The bottom line is how is it going to help us address the epidemic."
Dr. Deyton did not believe that DAIDS has used the committee well "to look at the bigger picture." There needs to be a proposal on the table and he is willing to work on one that considers issues such as strategic planning and individual program/project review, in addition to concept review.
Dr. Holmes said that a working group would be formed, consisting of those who express an interest in participating. Staff will query the member to their interest, by e-mail.
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