Adult AIDS Clinical Trials Group: Questions and Answers Concerning the Competitive Renewal.
1. What is the mission of the Adult AIDS Clinical Trials Group (ACTG)?
The Adult ACTG seeks to develop treatments that improve the quality and duration of life of HIV-infected adults. Specifically, the goals of the Adult ACTG are to:
- evaluate innovative therapeutic strategies and interventions to control HIV infection and its complications;
- facilitate rapid translation of basic research into clinical research and clinical practice; and
- provide a flexible resource for state-of-the-art, multidisciplinary, multicenter clinical trials that address the goals and objectives of NIAID's therapeutics research agenda.
2. What is the history and current structure of the ACTG?
The ACTG was established in 1987, building on NIAID's first major program for the evaluation of potential treatments for AIDS, which began in the summer of 1986. The original 36 AIDS Clinical Trials Units included two sites that enrolled children with AIDS. Additional pediatric sites were added between 1988 and 1989, and again in 1992. After a competitive renewal in 1992, the ACTG grew to include 35 adult and 22 pediatric AIDS Clinical Trials Units, in addition to a Statistical and Data Analysis Center and an Operations Office.
As a result of the recent competitive renewal, the Adult ACTG and Pediatric ACTG will operate separately. The new Adult ACTG includes 30 AIDS Clinical Trials Units, a Statistical and Data Management Center, and a Coordinating and Operations Center that will administer the Adult ACTG, provide scientific direction and perform advanced laboratory studies. The Pediatric ACTG includes 22 AIDS Clinical Trials Units, a Statistical and Data Management Center, and an Operations Center.
3. What is the chronology of the recent competitive renewal of the Adult ACTG?In 1993 NIAID began a comprehensive evaluation of the ACTG to assess the mission, scientific agenda, and future direction of the group, as well as its organizational structure and efficiency. Toward that end, the NIAID Division of AIDS established an external, ad hoc scientific review panel to evaluate the appropriateness of the ACTG's scientific plans, and an internal working group to evaluate organizational and managerial issues. A strong recommendation from both review groups was to clarify and strengthen the leadership of the ACTG, giving it increased authority to develop and manage its scientific program. The results and recommendations that came from these reviewers formed the basis for the competitive renewal of the ACTG.
NIAID published a Request for Applications (RFA) for the competitive renewal of the Adult ACTG in August 1994. In keeping with the recommendations from the review groups, several significant changes were incorporated into the RFA, the most salient of which were:
- the separation of the adult and pediatric research efforts, including governance and resources;
- the request for a Coordinating and Operations Center application, including a comprehensive research agenda, a designated Group Leader, and a central office for technical support; and
- an integrated review of the group's scientific agenda, management and leadership, and the individual clinical sites.
4. Why was a Coordinating and Operations Center application requested in the RFA and what did it encompass?
A strong recommendation from the two groups evaluating the ACTG was to strengthen the leadership of the group, giving them increased authority to develop and manage their scientific program. Another important recommendation, from the external ad hoc scientific review panel, was to comprehensively review the overall productivity and scientific plans of the cooperative group, linking the results of such a review with the competitive renewal process.
Therefore, the RFA requested that the Coordinating and Operations Center Application include: a comprehensive research agenda; the identification of a Principal Investigator who would serve as the Group Leader for the Adult ACTG; the proposed governing structure identifying key scientific and managerial leadership; an operations office for central technical and administrative support; a plan and proposed resources for centralized, advanced laboratory capabilities. Furthermore, the Adult ACTG RFA and review process included peer review of both the overall research agenda, and of the individual clinical sites in the context of the group's scientific goals and priorities. The group was thereby given increased responsibility and accountability for its operational and scientific plans. The group application was also designed to foster cohesiveness among Adult ACTG participants, especially among the scientific, statistical and managerial leadership.
5. How were applications in response to the Adult ACTG RFA reviewed?
Two separate committees reviewed the applications -- one committee reviewed and scored the applications for the Coordinating and Operations Center and the Statistical and Data Management Center (April 1995), and one reviewed and scored the institutional clinical site applications (May 1995). To avoid any conflict of interest, the committee that reviewed the institutional applications was subdivided into three panels, each of which reviewed one third of the individual clinical site applications.
The applications approved for further consideration, together with a summary statement, which contained a synopsis of the peer review evaluation and the priority score for each application, were then reviewed by the National Advisory Allergy and Infectious Diseases Council (September 1995) for a second level of peer review.
6. What review criteria were used to evaluate the proposals?
The basic review criteria for this RFA are the same as those for unsolicited research project grant applications, which include, among others:
- scientific, technical, or clinical significance and originality of the proposed research and the expertise / experience of key staff;
- appropriateness and adequacy of the experimental approach and methodology; and
- adequacy of plans for inclusion of women and/or minorities, especially in clinical trials.
In addition, the RFA requested specific criteria for each type of application, which included among others:
Adult ACTG Coordinating and Operations Center Application
- scientific, medical, and technical significance of the proposed research agenda, plans to effectively accomplish the scientific priorities, and experience of the leadership;
- adequacy of the proposed plan and budget for centralized, advanced technology laboratories;
- plans for overall group management and operations including the structure and mechanism for effective communication and collaboration among the group members; and
- plans for inclusion of women and underrepresented minority groups in clinical trials, and plans to include community representatives and to encourage the participation of new investigators, especially women and minorities, in research activities.
AIDS Clinical Trials Unit Application
- qualifications of key personnel, experience in multicenter HIV/AIDS clinical trials research, and scientific merit of the proposed contributions to the cooperative group consistent with the Adult ACTG Coordinating and Operations Center's scientific agenda;
- availability of a minimum of 75 new patients per year and evidence of the ability to accrue such patients; and
- previous experience and adequacy of plans for the inclusion of women and minority patients in clinical trials, for the participation of new and minority investigators, and for the involvement of community representatives in the sites' research activities.
Statistical and Data Management Center Application
- availability of experienced biostatisticians and other key personnel to provide statistical scientific leadership for the design and analysis of multicenter clinical trials;
- organizational structure, responsibilities, and procedures for communicating with collaborating institutions;
- plans for database design and administration, and procedures and policies for patient registration / randomization, data collection, management, analysis and quality control; and
- procedures for providing timely interim analyses of safety and efficacy and final analyses for publication.
7. How were these criteria determined?
The review criteria were developed to help ensure that the strongest applications, (i.e., those most capable of and likely to succeed at conducting high-quality, AIDS research), were identified. The Division of AIDS took several factors into account in developing the review criteria, including its experience managing the ACTG since 1987; the recommendations emanating from the Working Group on ACTG Organization and Management and the external ad hoc Scientific Review Panel; and the NIAID AIDS Research Advisory Committee (ARAC).
The criteria upon which proposals were evaluated were listed in the RFA.
8. Who was on the peer review committees?
The peer review committees were composed primarily of non-Federal experts who assessed the qualifications of each application based on the review criteria included in the RFA. Members included clinical and laboratory investigators, primary care providers, research staff, community representatives, and individuals with experience in working with racial/ethnic minorities.
9. What is the total amount of the Adult ACTG awards?
The NIAID and the National Institutes of Health are currently operating under a continuing budget resolution. Final funding amounts will be determined as soon as possible after a final FY 1996 budget is approved.
10. Why are there "set-aside funds" for minority institutions? What impact did this have on the Adult ACTG minority institutions?
In 1990, NIAID funded an initiative to assist minority institutions in further developing their expertise in conducting multicenter AIDS clinical trials, and in developing the necessary infrastructure. After a competition in 1993, four minority institutions were funded as Adult AIDS Clinical Trials Units. While they have been operating as ACTUs, these minority units have not had sufficient time to develop a highly competitive track record. Based on the demographic distribution of HIV/AIDS, these institutions, among others, are important to the Adult ACTG's ability to address critical research questions. Therefore, funds were set aside to ensure that applications from minority institutions would not have to compete directly for funds with other ACTU applicants, many of which had the opportunity to develop a track record over a much longer period of time.
11. Why are only 30 ACTUs being funded when the Adult ACTG previously had 35 units?
The final number of sites being funded through this RFA was determined by the number of applications of high merit and the amount of funds available.
12. Will the reduced size affect the ability of the Adult ACTG to accomplish its goals?
No. The RFA included a requirement for increased attention to pathogenesis-based clinical trials. Such studies tend to be smaller in size, although more laboratory intensive. The new structure and size of the Adult ACTG will enhance its ability to address these areas of high scientific priority, even though there will be fewer Adult ACTUs. The consolidated organization will allow the group to operate with greater efficiency and flexibility.
13. What role did geography and demographics play in site selection?
Each ACTU application had to demonstrate an ability to accrue a minimum of 75 patients per year and demonstrate that the site's patient population was representative of the HIV/AIDS population in its catchment area. Applicants were also instructed to address their plans for the inclusion of women and underrepresented minority populations in clinical trials. Reviewers evaluated the applications based on these criteria but did not specifically take geographic location into consideration. The predominant criteria for funding priorities were scientific and technical merit of the application in response to the RFA.
14. What role did NIAID staff play in the review process?
Division of AIDS program staff developed the initiative culminating in the release of the RFA, while the Division of Extramural Activities' Scientific Review Program was responsible for the conduct of the review. DAIDS program staff were available at the review as a resource to answer questions about the initiative and the overall program.
15. What data were available to the reviewers in addition to the submitted applications?
The Adult ACTG has two standardized instruments to evaluate the performance of the ACTUs. An annual report is issued to each Adult ACTU, which includes an evaluation of scientific contribution, compliance with protocol requirements and regulatory compliance. A monthly report is also issued to all Adult ACTUs, which evaluates each site's data quality and timeliness against group standards. Recent reports for incumbent Adult ACTUs were provided to the reviewers, together with overall group performance data. Applicants were provided with their respective data prior to the review and given the opportunity to respond; their responses were also provided to the reviewers.
16. What will the "phase-out" of unsuccessful incumbents involve?
Phase-out funding will be provided to all unsuccessful incumbent ACTUs for 12 months beginning January 1996. Once unsuccessful incumbent ACTUs are notified of their status, patient enrollment will be restricted to those protocols that will be completed by Sept. 30, 1996, including any follow-up. No new patients may be enrolled at these sites after Dec. 31, 1995.
The phase-out budget will be based on the number of patients who are participating in studies and the estimated number of months these patients will remain on the study. Prior to the end of the one year phase-out period, each protocol will be reviewed to determine if any of the phase-out sites have patients who will not have completed follow-up by September 1996. For those patients the options will include: transfer to another NIAID clinical trials unit, continuation on the study (for selected protocols) until the scientific needs of the study have been met, or discontinuation from study participation because the study outcome will not be compromised by loss of patients at phase-out sites.
17. What impact will the separation of the pediatric effort have on the Adult ACTG?
The Adult ACTG recompetition has resulted in the formal separation of the adult and pediatric research efforts, although the two groups have been, in effect, functioning separately since 1994. At that time, the adult and pediatric components of the ACTG established separate governing bodies, although they continued to share resources, namely, the ACTG Operations Office and the ACTG Statistical and Data Analysis Center. As a result of this competitive renewal, the resources for both groups will be distinct. Nonetheless, the Adult and Pediatric ACTGs will continue to have at least one joint meeting annually, as stipulated in the RFA, to ensure coordination and communication and will continue to have several shared scientific committees in areas where there is a high degree of overlap.
18. When will the Pediatric ACTG be competitively renewed?
The Pediatric ACTG will be competitively renewed in 1997.