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*Ad Hoc members
The National Advisory Council for Complementary and Alternative Medicine (NACCAM) convened at 8:30 a.m. on August 26, 2002, at the NIH Neuroscience Conference Center in Rockville, Maryland. Dr. Jane Kinsel, Executive Secretary, called the meeting to order.
The first portion of the meeting was closed to the public in accordance with the provisions set forth in Section 552b(c)(4) and 552b(c)(6), Title 5, U.S.C. and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix 2).
A total of 241 applications were assigned to NCCAM. Of these, 167 were reviewed by NCCAM, and 74 were reviewed by the Center for Scientific Review. Applications that were noncompetitive, unscored, or were not recommended for further consideration by the scientific review groups were not considered by Council. Council reviewed and concurred with 178 applications requesting $26,532,229 in total costs.
The open session of the NACCAM convened at 1:15 p.m. Dr. Jane Kinsel, Executive Secretary, called the meeting to order and reviewed the agenda for the open session. The members voted unanimously to approve the minutes of the previous meeting on May 28, 2002.
Dr. Stephen E. Straus, Director of the National Center for Complementary and Alternative Medicine (NCCAM), announced that the Secretary of Health and Human Services (DHHS) had officially appointed new council members. They include Dr. Zang-Hee Cho, Dr. Kristina Collins, Dr. Murray Goldstein, Dr. Michael R. Irwin, Dr. Barbara Timmerman, and Dr. Benjamin Chi-Kuo Yang. Dr. Straus welcomed the members and introduced the ad hoc members--Drs. Yung-Chi Cheng, Norman Farnsworth, Susan Folkman, Michael Hawkins, and Robert Wiltrout--to provide special expertise for the day's topics.
Dr. Straus introduced two new NCCAM senior staff members. Dr. Michael J. Quon joined the Division of Intramural Research; he is an internist and endocrinologist, and will apply his skills to understanding the cellular and metabolic consequences of various dietary supplements. Dr. Josh Berman is the new Director of NCCAM's Office of Clinical and Regulatory Affairs within the Division of Extramural Research and Training. He will help ensure the quality, safety, and integrity of NCCAM-funded clinical trials.
Dr. Straus presented an update on the Fiscal Year 2003 appropriations process. On July 18, the Senate committee approved a bill that would provide approximately $114.2 million for NCCAM--a 9 percent increase over the Center's FY 2002 appropriation. The House is expected to consider its version of the bill after the August recess.
Dr. Straus interrupted his remarks to introduce Dr. Elias Zerhouni, the new Director of the National Institutes of Health.
Dr. Zerhouni introduced himself to the Council and commented on the critical role he believes Advisory Councils play in ensuring that NIH Institutes and Centers (ICs) work effectively. Given the constantly changing state of science and its increasing complexity, NIH Advisory Councils face tremendous challenges. They must ensure that the quality and direction of science supports the needs of the American public. Dr. Zerhouni asked the NACCAM to consider how well the Center is balancing resources and output--an issue he is addressing by convening a series of group meetings to develop a road map for key NIH initiatives. Dr. Zerhouni also asked the Council to consider how NIH can improve access to new and emerging technologies. He would like their views on these and other issues. He then opened the floor to questions and comments.
One Council member asked Dr. Zerhouni if he was considering creating an inter-council group that would allow select members of ICs' Advisory Councils to discuss trans-NIH responsibilities and issues. Dr. Zerhouni said that he wants the Councils to know what their counterparts are doing and that, for scientific reasons, enhanced inter-Council communication is a necessity. Another Council member asked Dr. Zerhouni what his first priorities are for the NIH. Dr. Zerhouni replied that the NIH ICs need strong leadership. Thus, his first priority is to appoint new directors for those ICs that currently have vacancies. Lastly, another Council member mentioned that there is much high quality research related to CAM that is left unfunded under the current budget.
Dr. Straus thanked Dr. Zerhouni and continued with his comments. In early August, NCCAM and the National Heart, Lung, and Blood Institute (NHLBI) funded a chelation therapy trial, which will enroll 2,300 participants at 100 research sites around the country. NCCAM is also collaborating with the National Institute of Allergy and Infectious Diseases to establish the Preclinical Antiviral Testing Program for CAM.
This joint effort, in which the U.S. Army Medical Research Institute on Infectious Diseases is also a co-collaborator, will test potential antiviral agents (including natural and synthetic compounds that qualify as CAM) in vitro for their activity against numerous types of viruses. This screening program, which will emphasize the selection and screening of agents that may be used to prevent and/or treat infectious diseases capable of being used as weapons of war or terror and HIV, should provide the scientific community with invaluable information about various compounds and expedite the research process.
Dr. Straus provided an update on the R25 educational grant program. Three years ago, NCCAM announced its intention to fund 15 awards over 3 years (5 years each) with the goal of integrating CAM into predoctoral education curricula. All of these awards have been made. Members of the CAM research community have inquired about the next generation of R25 awards. After completing the extensive planning process for Fiscal Years 2003 and 2004 and completing a major review of the Centers program, NCCAM has decided to assess the success of the current R25 program before committing to another education initiative. In the interim, NCCAM plans to invest in a more direct and productive way to develop research infrastructure at CAM institutions through its Centers program.
Dr. Straus provided an overview of the recent review of NCCAM research centers, beginning with his meeting with the directors of the current centers in March 2002. He introduced Dr. Susan Folkman, Director of the Osher Center for Integrative Medicine at the University of California, San Francisco and a member of the expert panel that met in June to review NCCAM's research centers program, who presented the panel's final report to Council.
Expert Panel Report
In the course of their review, Dr. Folkman explained that the members of the expert panel considered the role of the research centers in advancing NCCAM's mission in the future, important features for future centers, and the funding mechanisms best suited for various types of centers conducting CAM research. To date, the panel concluded that NCCAM's current research centers have a mixed record: they have excelled at furthering the visibility and credibility of CAM research, building research infrastructure, and drawing investigators into the field, but have not yet established a strong record of research accomplishments and publications.
One of the panel's primary recommendations was that future NCCAM research centers be organized around a specific theme, focusing on particular diseases, groups of therapies, or the mechanisms of action of CAM therapies.
In addition, the panel suggested that NCCAM adopt a more flexible approach to funding, using mechanisms other than the P50 award, especially those that encourage autonomy of experienced investigators on the one hand and other mechanisms that provide greater opportunities for investigators at CAM institutions. The panel also recommended that future research centers incorporate more basic science research, provide opportunities for investigators to conduct pilot projects, continue to provide research support and infrastructure, and devote more resources to developing standardized therapies. Finally, the panel called for future centers to develop strategies for timely IRB approvals, involve CAM practitioners as investigators, provide career development opportunities for both CAM and conventional researchers, and offer the option of conducting health services research.
Concept Review: Research Centers
Dr. Christine Goertz of NCCAM explained that the expertise of investigators who might study CAM ranges from novice to highly sophisticated. To this end, she presented a multifaceted approach to supporting future NCCAM research centers, represented by two separate concept proposals for the Council's review.
The first, Centers of Excellence for Research in CAM, is intended to support CAM research in established research institutions. These CAM Research Centers would be funded using the P01 program project award mechanism, which supports broad-based multidisciplinary research programs with a well-defined central research focus.
The second proposal, Developmental Centers for Research in CAM, would provide the infrastructure necessary to build and foster research collaborations between CAM and conventional institutions. The program goals would be to conduct synergistic exploratory/developmental research projects and to facilitate development of the capacity of CAM institutions and investigators to participate in the CAM research enterprise. These Developmental Centers would be funded under the U19 Cooperative Agreement mechanism and would require a high level of NCCAM staff involvement. Partnership with conventional institutions is a key feature.
Discussion
Dr. Straus noted that NCCAM currently supports 12 P50 centers. The expert panel recommended other funding mechanisms in part because P50 grants support a range of activities--outreach, publications, etc.--that have diverted the attention of researchers. The P01 and U19 focus primarily on research and are much more structured. In order to allow for long-term planning, NCCAM is considering issuing these concepts as multi-year program announcements.
There was some concern expressed that P01 awards would provide few resources for research training, despite the fact that one of NCCAM's missions is training. However, Dr. Straus explained that NCCAM is meeting the need for training with other career development opportunities, and has increased tenfold its investment in training grants.
The concepts were approved.
Dr. Straus noted that NCCAM has been concerned about the products it tests in clinical trials, and the discussion has been shaped by Council's input regarding what constitutes adequate characterization of products and oversight. This is a crosscutting issue for NIH as a whole. NCCAM must ensure that it puts in place adequate protective measures. To that end, NCCAM has established the Office of Clinical and Regulatory Affairs (OCRA). Dr. Josh Berman, Director of OCRA, spoke on NCCAM's product evaluation efforts.
Clinical trials are required for a thorough evaluation of a product or practice. Phase 1/2 trials are needed to identify an optimum dose. The dose currently used may be too high and toxic, or too low and ineffective. In subsequent Phase 3 studies, the apparently optimum dose from Phase 1/2 studies is investigated with sufficient numbers of subjects so that efficacy and toxicity can be determined with statistical confidence. Phase 3 studies are needed to be able to confidently recommend a dose regimen for general use.
An important preliminary issue is the chemical-manufacturing and preclinical/animal background data needed to support NCCAM's Phase 1/2 clinical trials. All products studied in NCCAM-sponsored trials will have been in use for some time. If the prior clinical use has been substantial and gives considerable clinical confidence in the product, less chemical-manufacturing data is needed to support initial clinical trials. The FDA has drafted guidance that can help us adjust chemical-manufacturing standards that are in place for synthetic drugs to botanicals with prior clinical use. Since PHS 398 instructions indicate that NCCAM botanical drug protocols must be submitted to the FDA for their determination if an IND is required, following FDA guidance will be additionally useful if the FDA requires an IND.
Once it is decided that a clinical study should proceed, protocols must be written and reviewed as well as monitored during the study to protect patients and to ensure that the study is achieving its intended goal.
Good Clinical Practices (GCP) have been devised and are in use worldwide so that organizations conducting clinical studies can best ensure ethical trial conduct and data accuracy. To ensure that NCCAM's clinical trials comply with GCP, Data Safety and Monitoring Plans need to be submitted and reviewed.
The discussion began with a focus on standardization of product, both single and multiple agents. Dr. Berman will be working with the Office of Dietary Supplements (ODS), NIH on these issues. Consistent agriculture practices are necessary for botanicals but difficult to achieve, especially when researchers do not know the active compounds, which could serve as markers. Dr. Straus mentioned that all clinical studies supported by NCCAM have been approved by an Institutional Review Board (IRB), and therefore need a Data Safety and Monitoring Plan, although not all need a Data Safety and Monitoring Board.
To help with the success of trials, OCRA will disseminate guidelines for the background information that applicants might include in their grant application, along with general principles of study design, and will help with trial oversight.
Collaborations with industry were discussed. In May 2001, NCCAM convened a meeting with industry representatives to learn about their capabilities and areas of potential mutual interest. There is no obligation for botanical products to be developed as drugs per se, but Council members thought that industry might wish to work with NCCAM in formally developing botanical products.
NCCAM had awarded funds for four studies on PC SPES--three laboratory studies and one clinical study. The laboratory studies were underway when the California Department of Health detected undisclosed drug contaminants in multiple lots of PC SPES; the manufacturer voluntarily recalled the product. At the Council meeting of May 28, Council's advice on this issue was solicited. The Council was clear about NCCAM's responsibility and the need to ensure the safety of study participants and the integrity of study results. Therefore, Council urged NCCAM to put the studies on hold pending further discussion.
Over the summer, NCCAM took a series of steps to gather more information. In June, NCCAM informed the investigators that NCCAM intended to put studies on hold and posted a consumer advisory on its Web site. A July teleconference with investigators focused on how they would characterize their product and interpret the data. The investigators felt the data could provide meaningful information despite the product quality concerns. In August, NCCAM convened an ad hoc working group, including two Council members--Col. Williams and Dr. Kaptchuk--several investigators, oncologists, and urologists for advice. On the basis of these meetings, NCCAM developed a statement that there were important opportunities with PC SPES to pursue and, therefore, the preclinical studies could proceed but the clinical trial would be terminated. Dr. Straus asked Council for a recommendation on this planned approach.
Col. Williams presented the view that hundreds of men were taking PC SPES and it seemed to be helping. The patients have been left in a situation without the one thing they thought was benefiting them. He was encouraged by what NCCAM has done so far and urged that the problems be resolved as quickly as possible.
Although PC SPES was marketed as a dietary supplement, it was patented for and claimed to treat prostate cancer. NCCAM is studying some of the individual components, but the Center is unable to study the product as the manufacturer has ceased operations and product is unavailable. Patent infringement issues may be significant impediments to a private sponsor making the formula. As similar, but not identical, products become available, investigators must study the product more extensively before proceeding to a clinical trial, which could take several years.
Dr. Straus asked if the Council agreed with the proposed statement. The alternatives are to terminate all studies, continue all studies, or allow only the laboratory-based studies to continue. The investigators can spike the test medication in the preclinical trials with the contaminant in order to study what effect the contaminant has. Col. Williams agreed, but wondered if the prostate cancer patients who wish to do so could sign a waiver and participate in trials at this time. Dr. Straus explained that there must be a manufacturer and a product in order to conduct a clinical trial. An IRB would not likely allow a continued study. Council concurred with the third alternative.
As required by law, NCCAM set aside time for public comment.
Dr. Fulton Sayer of Portland, OR, spoke in favor of PC SPES. He is a board-certified obstetrician/gynecologist and has done his own research on the product. He presented a graph showing how his own PSA levels went from over 50 to nondetectable after using PC SPES. This is concomitant with a significant decrease in the size of the prostate gland. He was amazed and skeptical. It raises many questions for further research: What is the mode of action? What is its longevity of remission? There are testimonials, but data are needed. He is one of a group of men forming an organization, Natural Approaches to Prostate Cancer, Inc. They want to bring back uncontaminated PC SPES quickly, support research, and make it available. The holder of the patent has offered no-cost licensing of her patent to them. They want to work with NCCAM and the government in full cooperation.
Mr. Chris Williams represents the European part of the organization mentioned by Dr. Fulton. He has an identical graph on metastasized prostate cancer responding to PC SPES and attributes his survival to PC SPES. He asked for NCCAM's support to get a PC SPES analog on the market soon. He plans to talk with manufacturers. The objective is to get the product back as soon as possible, and to obtain FDA approval.
Mr. Michael McGuffin, of the American Herbal Products Association, said that there is a great deal of interest in the industry to solve this problem. Much has been done to try to move this forward. What his group has seen is a strong industry interest in bringing resources forward to recreate the formula. The patent issue must be more fully explored.
Mr. Bob Herman, with the same patient group as Dr. Fulton and Mr. Williams, showed a graph of his improvement. The urgency is an issue; he has gotten many phone calls, often from wives and children of prostate cancer patients, asking what they can do.
After the public comment session, the meeting was adjourned at 5:15 p.m.
We hereby certify that, to the best of our knowledge, the foregoing minutes are accurate and complete.
Jane F. Kinsel, Ph.D.
Executive Secretary
National Advisory Council for Complementary and Alternative Medicine
Stephen E. Straus, M.D.
Chair
National Advisory Council for Complementary and Alternative Medicine
Resize text: SML This page last modified December 01, 2008.
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