Oncology Nursing Society (ONS). Ms. Deborah Mayer, Chief Medical Officer, Cancer Source.com, reported that the meeting was well-attended. She noted that problems with IRBs concerning multi-site, multi-institutional outcome studies were becoming significant barriers to moving forward some of the research that was ongoing within and outside the ONS.
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V. UPDATE: MOUSE MODEL INITIATIVE - DR. CHERYL MARKS
Dr. Cheryl Marks, Associate Director, Office of the Director, Division of Cancer Biology (DCB), reminded Board members that the concept for the Mouse Model Initiative was approved by the BSA in March of 1998. Dr. Marks reported that the RFA was advertised in July of that year, and of the 31 applications received 18 were funded; eight of those were cooperative agreements (U01s) and one was a large intramural project on breast cancer. As of July 1, 2000, the Mouse Models of Human Cancer Consortium will be completed with the addition of a Department of Defense-funded project to model neurofibromatosis I and II in the mouse. Members were told that the Mouse Models of Human Cancer Consortium structure includes eight disease site-specific committees, which serve as bridges to other cancer research community components. Six standing committees provide resources and address issues that span all of the disease sites.
Dr. Marks stated that of the original consortium goals, the most important is to develop and implement a flexible community-based infrastructure to allow: (1) continuing validation of models, (2) setting the standards for this continuing validation, and (3) reaching out to the community so the needs for various applications of these models can be met and can be integrated with the rest of the cancer research community. Dr. Marks described the ongoing activities of the various groups and committees in the consortium, such as the Central Nervous System (CNS) Tumors Group, the Hematopoietic Malignancies Group, the Breast Cancer Models Group, the Technologies Committee, and the Preclinical Trials Committee. She noted that a mouse engineering workshop will be held at one of the AACR meetings, and a hands-on modeling laboratory will be held at Jackson Laboratories in the fall for colon cancer models.
Following a presentation of the Mouse Models of Human Cancer Consortium to the imaging community, Dr. Marks stated that the imaging community expressed interest in learning the biology of the mouse to ensure that new mouse models incorporate the kinds of tags and markers that would allow them to image these models as soon as possible. Dr. Marks noted that although the consortium includes 20 groups and about 60 or 70 collaborators, input from the rest of the community is needed. Input is gained through: (1) consensus workshops sponsored by the Consortium; (2) a recently established repository at the NCI Frederick facility; and (3) several databases that are being formulated. The Consortium also is going to link to a database at the Jackson Laboratories and is establishing links with the American Society for Hematology and the Leukemia and the Lymphoma Society. The intent is to use these Web sites for a leukemia and lymphoma vocabulary project, which the Consortium's Hematopoietic Malignancies Group is developing. A Mouse Implementation Group, which has members from the various NCI Divisions, has been established.
In discussion, the following points were made:
- The Consortium was instrumental in helping the NIH, NCI, and DuPont come to an agreement regarding the onco-mouse patent. Other pharmaceutical companies have approached the Consortium to collaborate in the development of therapeutics.
- Board members were asked to suggest effective ways to inform the community about the activities of the Mouse Models of Human Cancer Consortium. Suggestions should be sent to Dr. Cheryl Marks, DCB, NCI.
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VI. PROPOSED RFA/COOPERATIVE AGREEMENT CONCEPT - PRESENTED BY NCI PROGRAM STAFF
Division of Cancer Control and Population Sciences
Population-Based Cancer Care and Outcomes Research and Surveillance Consortium (CanCOR) (RFA/Coop.Agr.) Dr. Barbara Rimer, Director, Division of Cancer Control and Population Sciences (DCCPS), stated that this initiative is central to a number of the challenges and opportunities that are in the ByPass Budget. The initiative will examine the dissemination of cancer treatment across different kinds of treatment settings, situations, and cancers. It will also look for ways to study health disparities in cancer care and is tied to the continuing challenge of identifying and tracking emerging cancer trends. CanCOR will be focusing on lung cancer and colorectal cancer. Studies of these cancers are particularly helpful when examining health disparities. Dr. Rimer noted that being able to compare the treatments that men and women receive is another appealing aspect.
Dr. Rachel Ballard-Barbash, Associate Director, Applied Research Program, DCCPS informed members that staff had addressed Board members concerns from the last Board meeting by: (1) clarifying the goals, (2) assuring data standardization, (3) addressing quality control and feasibility, and (4) clarifying what will comprise the core research effort. She referred to the SEER patterns of care effort to illustrate that feasibility and standardization are possible for large-scope efforts across diverse practices.
Dr. Arnold Potosky, Senior Investigator, Health Services and Economics Branch, DCCPS, further reviewed several ways in which the concept had been modified in response to concerns and suggestions raised at the previous Board meeting. Dr. Potosky stated that the concept goals had been changed to more clearly reflect the broad areas of investigations that are going to be pursued. He reviewed amendments and clarifications in the following areas: (1) prospective measurements of processes of care in newly diagnosed cancer patients, (2) the necessity of linking these processes of care to best identify what constitutes good quality of care, and (3) investigating health disparities as an NIH challenge area. Members were told that the overall aim of the CanCOR Consortium is to support innovative research to move beyond the description or the identification of disparities in treatment and care. The intent is to understand the causal factors, which may be related to variations in care, and the extent to which such variations may be contributing to poorer outcomes in vulnerable populations. To demonstrate the feasibility of this effort and its implementation possibilities, a staged approach with two types of cancer, lung and colorectal, was adopted. Another major change is encouraging applicants to consider factors beyond cancer patient barriers to care, such as the clinical or nonclinical characteristics of patients, and to focus on provider knowledge, attitudes, practices, and health system factors that also may be importantly related to who receives high quality cancer care.
Dr. Potosky stated that CanCOR will support large prospective studies in cohorts of approximately 6,000 lung and colon cancer patients. To help ensure the standardization of data collected by this Consortium: (1) each of the five to seven research teams will collaborate with one another and will identify core measures to be collected by all the research teams; (2) a single statistical coordinating center (SCC) will cover both lung and colorectal cancer; (3) the SCC will develop data dictionaries, informatics, and software that will be used by all the research centers; and (4) a data standards committee, chaired by the PI of the SCC and including representatives from each of the research centers, will establish quality control procedures to be used in the collection of abstract medical record and survey data.
The estimated cost of CanCOR over its 5-year period is $40M . At the BSA meeting next March, plans are to propose a second RFA concept for breast and prostate cancer, which will probably have more emphasis on the study of prognostic factors beyond treatment.
In discussion, the following points were made:
- Applicants to this RFA could include academic institutions, cancer centers, state agencies, professional managed care organizations, collaborative groups, Community Clinical Oncology Programs, large health care delivery organizations, and professional societies. The concept encourages partnerships with population-based tumor registries.
- A cohort of a population is not necessarily population-based, and even if the demographics are balanced, it is not population-based if it requires hospital, patient, and physician consent for participation. One of the ways to provide population based analyses is to define in the RFA that applicants are sought who could accrue patients from diverse socioeconomic backgrounds and minorities.
- A health disparities presentation will be given at a future Board meeting.
Motion: A motion to accept the Cooperative Agreement concept entitled "Population-Based
Cancer Care Outcomes and Surveillance Consortium (CanCOR)" as written, taking into consideration the comments of the Board, was approved with one member opposed and four abstentions. Specifically, pilot projects should be included during the first year to assess feasibility; hypotheses driven research should be emphasized; study populations must be diverse; additional funds should be directed toward the statistical center; and input should be sought from patients, advocacy groups, and people at the community level.
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VII. PROGRESS REPORT: CLINICAL TRIALS RESTRUCTURING - DR. JEFFREY ABRAMS
Dr. Jeffrey Abrams, Senior Investigator, Clinical Investigations Branch, Clinical Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis, informed BSA members that some of the large projects underway in clinical trials restructuring involve redoing some of the Phase III or larger trials and developing ideas for these trials. Dr. Abrams stated that instead of the traditional cooperative group strategy meetings, state-of-the-science meetings, which are open to a broader audience, are now being held. Once ideas for Phase III trials surface, they can be submitted for a concept review. After concepts are approved and become protocols, they move into the Cancer Trials Support Unit (CTSU). It is hoped that this process will be expanded to include investigators from outside the cooperative groups who would use the CTSU as a "one-stop shop" for the management of clinical trials. An investigator participating in four or five trials led by different groups would not have to deal with the mechanisms of each group. There would be a common mechanism and, hopefully, this will reduce some of the barriers to participation. In the next step of this process, concepts are forwarded to Concept Evaluation Panels (CEPs). Traditionally these kinds of NCI reviews have been conducted in-house within the CTEP; however, in this program the CEPs are composed of one-third NCI members and two-thirds outside members from cooperative groups, cancer centers, basic researchers, and patient advocates. Dr. Abrams noted the pilot nature of this effort and described the online review tool and scoring system that has been developed. Once the concepts are approved, and if there are available protocols, they go into the CTSU.
The state-of-the-science meetings that have been held and are planned were described. Dr. Abrams indicated that a Web site had been developed to ensure that the results and ideas from these meetings are disseminated. As of April 2000, the site has progressed from 100 to 200 hits per day to nearly 10,000 hits per day.
Dr. Abrams indicated that $31M of the approximately $60M was being used to support leadership activities, cooperative groups to help them modernize their systems, and patient reimbursements. The remainder is being used to fund a subcontract to support centralization of the databases for all cooperative groups, IRB databases, audit management, and establish uniform training and education as well as promote the trials.
In discussion, the following points were made:
- Cost per patient associated with this program is expected to be $15,000. Once this program enters a maintenance phase and the startup costs are minimized, the cost per patient will be reduced.
- New policies related to the conduct of clinical trials and clinical trial research will be presented to the Board at a future BSA meeting. Specifically, staff should address safety and data monitoring, the role of IRBs, and education/training of principal investigators regarding adherence to clinical trial protocols.
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VIII. PROPOSED RFA CONCEPT - PRESENTED BY NCI PROGRAM STAFF
Office of the Deputy Director for Extramural Science
Innovative Cancer Complementary and Alternative Medicine (CAM) Initiative in Cancer Centers (RFA): Dr. Jeffrey White, Director, Office of Cancer Complementary and Alternative Medicine, stated that the purpose of this initiative is to encourage and support therapeutic, basic , epidemiologic, clinical prevention, palliative, and population-based cancer research within NCI-supported cancer centers. The intent is to: (1) facilitate communication and collaboration between CAM practitioners and the conventional cancer research communities; (2) support pilot projects that have the highest likelihood of being developed into successful R01 investigator-initiated applications; and (3) to assist NCI's designated Cancer Centers in building their CAM research capabilities. Dr. White informed Board members that there is a paucity of data available to indicate whether many CAM practices are efficacious or safe; despite this, there is large-scale use of many of these approaches throughout the United States, and there is every indication that use of these practices is growing among cancer patients.
The proposed RFA will fund supplements to clinical and comprehensive P30 cancer center grants. A competitive peer review will be conducted by an NCI special emphasis panel with input from the National Center for Complementary and Alternative Medicine (NCCAM). The proposed length of award is 3 years with a first year set-aside of $2M and a total cost of $6M. The projected budget will be shared equally by the NCI and NCCAM. Each application will contain up to three pilot projects, and each award would provide up to $300,000 in total costs. The initiative is limited to the clinical and comprehensive cancer centers to allow for the efficient facilitation of the establishment of collaborations between research-intensive organizations and the practitioner and academic CAM communities.
In discussion, the following points were made:
- Between one-half and two-thirds of cancer patients use complementary medicine as part of their treatment, much of which is unregulated, untested, and of unknown benefit and risk.
- The definition of CAM needs to be clearly articulated and the initiative may be more successful if two projects, rather than three, are funded.
- In addition to a focus on CAM's safety and efficacy, applicants should be encouraged to address research in the following areas: (1) integrating CAM with conventional cancer therapy; (2) delivering CAM; (3) educating and communicating CAM therapies and their optimal use to cancer patients, survivors, and the public; (4) elucidating special approaches to psychosocial and practical aspects of CAM therapies; and (5) credentialing CAM research.
Motion: A motion to approve the letter RFA concept entitled "Innovative Cancer
Complementary and Alternative Medicine Initiative in Cancer Centers" was unanimous. The
concept, however, should be revised to: (1) more clearly define complementary and alternative
medicine (CAM); (2) more clearly define the research questions; (3) emphasize the need for
rigorous study design; (4) encourage collaborations among Cancer Centers; (5) allow two
projects, rather than three; (6) clarify that NCI will submit any required investigational new drug
(IND) applications; (7) emphasize integrating CAM with conventional medicine; (8) address
oversight and quality control; and (9) highlight efficacy and the pathophysiology of
comp
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lementary approaches to pain management.
IX. PROPOSED COOPERATIVE AGREEMENT CONCEPT - PRESENTED BY NCI PROGRAM STAFF
Division of Cancer Prevention
Collaborations on Nutritional Modulation of Genetic Pathways Leading to Cancer (Coop. Agr.): Dr. John Milner, Acting Chief, Nutritional Sciences Research Group, stated that this concept, developed by the Nutrition Science Research Group, is aimed at establishing interdisciplinary collaboration to expand and facilitate research dealing with the precise role that diet has in the cancer process. Dr. Milner explained that the concept builds on a wealth of information from a variety of sources suggesting that diet can be a key factor regulating overall cancer risk. Data arising from epidemiological and animal studies suggest that a variety of nutrients may modify one or more phases of the cancer process. Certain nutrients may increase cancer risk in some cases, but in other circumstances, these same nutrients may decrease cancer risk. This concept is an effort to move the science of nutrition from observation to probing studies that will identify those individuals who would benefit from nutritional intervention and those individuals who might be placed at risk by dietary intervention. Genetic pathways play a key role in deciding the overall response to a nutrient. This concept will also capitalize on the special expertise and talents of the investigators and allow them to embody the newest and most innovative techniques to address the role of diet in gene regulation and genetic pathways. Four broad areas that might be appropriate to address are: (1) methylation patterns as they relate to phenotype; (2) the nutrients that modify the balance between differentiation, growth, and apoptosis; (3) antioxidants or oxidative stress; and (4) folates.
The proposed two-phased approach is a six month planning period (Phase I) and a four year collaborative project (Phase II). The P20 planning grant mechanism will be used for Phase I and the U54 grant mechanism will be used for Phase II. The intent is to fund twelve 6-month Phase I studies at $100,000 per year. The number of projects would be reduced to six during Phase II, with approximately $1.75 million awarded to each of the six projects per year. The estimated first year set-aside is $1.2 M and a total cost of $45.1M over 5 years is anticipated.
In discussion, the following points were made:
- The project might be more successful if it began on a smaller scale, i.e., build a pool of investigators who have a proven track record in the combination of necessary skills.
- The mechanism by which these investigators come together for these collaborative projects, the nature of the collaboration, and whether these grants will be P01s or R01s should be made clearer.
Motion: A motion to approve the Cooperative Agreement concept entitled "Collaborations on
Nutritional Modulation of Genetic Pathways Leading to Cancer" was amended to specify that the concept be funded at half the requested amount. Approval of additional funding would be dependent on the evaluated success of the initial projects. The amendment was passed unanimously. The motion to accept the concept, as amended, was approved with one abstention.
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X. PROPOSED RFA CONCEPT - PRESENTED BY NCI PROGRAM STAFF
Division of Cancer Treatment and Diagnosis
Technologies for Comprehensive, Quantitative Protein Analysis in Human Tumors (RFA):
Dr. James Jacobson, Chief, Technology Development Branch, Cancer Diagnosis Program, stated that the goal of this initiative is to stimulate the development of novel innovative technologies for the quantitation of the spectrum of proteins that are expressed in human tissues. It is anticipated that the technologies developed would provide both the identity and the relative abundance of each protein detected and analyzed. Dr. Jacobson explained that the protein technologies available for comprehensive analysis are not very quantitative and there is a real need to promote quantitative technology development. Comprehensive data about the ribonucleic acid (RNA) and protein expression are needed to determine what is happening at the functional level, particularly when trying to take these comprehensive protein analyses and organize them into cellular pathways and understand how those pathways are functioning in tumors. It is hoped that this concept will challenge the community to propose novel approaches to developing these technologies, going beyond the incremental improvements in technologies to facilitate some new approaches that may be high risk but have the potential for moving the field forward substantially.
The proposed length of award is 5 years with a first year set-aside is $1.5M and a total cost of
$6.5M for an estimated 5 R21/R33 awards.
In discussion, the following point was made:
- The issue of adequate sensitivity must be considered.
Motion: A motion to accept the RFA entitled "Technologies for Comprehensive, Quantitative
Protein Analysis in Human Tumors" was unanimously approved. To pick-up the differences in proteins that are likely regulatory enzymes, sensitivity should be included.
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XI. SMALL ANIMAL IMAGING RESOURCE PROGRAMS: INITIAL EXPERIENCE C DR. DANIEL SULLIVAN
Dr. Daniel Sullivan, Associate Director, Biomedical Imaging Program, presented an update on the Small Animal Imaging Programs, noting that the results after less than one year of existence have been impressive. The purpose of the RFA was to provide: (1) an imaging resource to oncology researchers, and (2) a laboratory for the research and development of small animal imaging technologies. Dr. Sullivan said there was initial skepticism as to whether imaging researchers would be willing to devote half of their time to providing this resource to other researchers when they have to worry about their own careers and academic advancement; however, initial results suggest that this is not a major concern. In the original RFA, applicants had to have experience with small animal imaging and an existing imaging resource. It was required that they add one additional resource because the prevailing mature technology was magnetic resonance imaging (MRI) and the intent was to have other imaging technologies involved. Investigators had to provide imaging services to three oncology collaborators by the end of the first year and six by the start of the third year. Dr. Sullivan reported that a total of five MRI programs were funded from that first RFA. All are providing an aspect of radionucleid imaging, and four of the five are providing derivatives of optical technologies, including bioluminescent imaging. The five programs are currently collaborating.
Dr. Sullivan provided Board members with examples of the work completed to date. He discussed how tumor growth data derived from these programs have been useful to certain research projects. He also noted that the imaging techniques and technologies being developed and/or perfected can detect tumors that are a submillimeter in size. These imaging technologies also allow researchers to follow tumors back to earlier time points when it is almost invisible, calculate the growth rate for all individual tumors, and acquire data that are not possible to acquire by sacrificing the animal at individual time points. Dr. Sullivan noted that the animals in these studies have to be anesthetized and ventilated, cardiac rates and respiratory rates have to be monitored, and they must IVs. He stated that there are not enough people experienced and trained in these issues, and that future workshops and training opportunities could come under the auspices of this program if it expands in the future.
Dr. Sullivan explained that the optical techniques used in this program are very effective tools, particularly in mice. It is less clear how effective they would be in humans. The RFA will be reissued next fiscal year and a requirement for training, both for professional and technical staff will be added.
In discussion, the following points were made:
- There is much interest in scaling up the MRI and positron emission tomography methodologies and making them feasible in human patients. For optical technologies, it is less clear as to whether they can be used effectively in human tumor research, diagnosis, and treatment. Additional programs to help facilitate the interaction between engineers who are working on the technologies and clinicians who could see the potential applications may be planned.
- If this program is successful, it may be expanded and modified by adding training and other components without the consent of the BSA.
Adjournment: The meeting was adjourned at 4:18 p.m. on Thursday, June 22, 2000.
Frederick R. Appelbaum, M.D.
Chair, Board of Scientific Advisors |
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Paulette S. Gray, Ph.D.
Executive Secretary
Board of Scientific Advisors |
