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Minutes of Special Conference Call Meeting - March 17, 2003
National Advisory Council for Complementary and Alternative Medicine (NACCAM)
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NACCAM Members Participating
- Dr. Julie Buring, Boston, MA *
- Dr. Zang-Hee Cho, Irvine, CA
- Dr. Kristina Collins, McLean, VA
- Dr. Murray Goldstein, Washington, DC
- Dr. Michael Irwin, Los Angeles, CA
- Dr. Janet Kahn, Burlington, VT
- Dr. Konrad Kail, Phoenix, AZ
- Dr. Ted Kaptchuk, Boston, MA
- Dr. John Longhurst, Irvine, CA *
- Dr. Tieraona Low Dog, Albuquerque, NM *
- Dr. William Meeker, Davenport, IA
- Dr. Barbara Timmerman, Tucson, AZ
- Dr. Myron Weisfeldt, Baltimore, MD *
- Col. James Williams (Ret), Camp Hill, PA
- Dr. Benjamin Yang, San Francisco, CA
* Ad hoc members
Note: Drs. Buring and Goldstein participated in person. Other members participated by conference call.
NACCAM Members Absent
- Dr. Haile T. Debas, San Francisco, CA
NIH Staff Present
National Center for Complementary and Alternative Medicine (NCCAM)
- Dr. Margaret Chesney, Deputy Director
- Ms. Linda Engel
- Ms. Carol Fitzpatrick-Mulligan
- Dr. Martin Goldrosen
- Ms. Anita Greene
- Ms. Mary Jo Hoeksema
- Ms. Camille Hoover
- Dr. Jane Kinsel
- Mrs. Marguerite Klein
- Dr. Richard Nahin
- Dr. Nancy Pearson
- Dr. Stephen Straus, Director
- Dr. Shan Wong
Other NIH Staff
- Dr. Joseph Betz, OD/Office of Dietary Supplements (ODS)
- Dr. Paul Coates, OD/ODS
- Dr. Sheryl Rosenthal, OD/ODS
- Dr. Anne Thurn, OD/ODS
Members of the Public
- Ms. Patricia Beaston-Wimmer, Food and Drug Administration
- Ms. Susan Bramas, Federal Trade Commission
- Dr. Steven Dentali, American Herbal Products Association
- Dr. John Hathcock, Council for Responsible Nutrition
- Mr. Richard Kelly, Federal Trade Commission
- Ms. Joni Lupovitz, Federal Trade Commission
- Dr. Cazemiro Martin, Food and Drug Administration
- Mr. Bryon Powell, Hymon, Phelps and McNamara
- Ms. Alexandra Sorensen, Patton Boggs
The National Advisory Council for Complementary and Alternative Medicine (NACCAM) convened in open session at 2:00 p.m. on March 17, 2003, at the NIH Neuroscience Conference Center in Rockville, Maryland. Dr. Jane Kinsel, Executive Secretary, called the meeting to order.
I. Call to Order and Opening Remarks
Dr. Jane Kinsel opened the meeting by taking a roll call of those participating by phone, and then introduced those in the meeting room. This special session was open to the public. Dr. Kinsel reviewed the materials sent to the Advisory Council members in advance of the meeting and available at the meeting. These included a copy of the agenda, a roster of Council participants, the report of the Ephedra Working Group, two recent articles from the Journal of the American Medical Association, a study concept document, and recent fact sheets on ephedra issued by the Department of Health and Human Services (DHHS) and the National Center for Complementary and Alternative Medicine (NCCAM).
Dr. Stephen Straus, Director of NCCAM, outlined the agenda for the conference call. First, the Council would hear the report of the special Working Group assembled to review the existing evidence on the safety and efficacy of ephedra. The Working Group was charged to discuss clinical and methodological issues, as well as research gaps, and to make recommendations for further research, if any, to more completely delineate the safety and efficacy of ephedra-containing dietary supplements.
The background to assembling and charging the Working Group was as follows. Over the past several years there had been reports of adverse events arising in people who consumed ephedra products. In 2001, a consumer group asked FDA to halt the sale of ephedra. Regulation of products falls to the Food and Drug Administration (FDA). To help understand ephedra better the Department of Health and Human Services asked NIH whether the reports could be reasonably attributed to it. To this end, NCCAM and the NIH Office of Dietary Supplements in response, requested and funded a comprehensive review of the available published and unpublished evidence regarding the safety and efficacy of ephedra and ephedrine through the Agency for Health Research and Quality's (AHRQ) Evidence-based Practice Center at RAND-Southern California. The written report of this review was completed in January 2003, published in the JAMA in March 2003, and constituted one of the primary background documents for the Ephedra Working Group.
Dr. Julie Buring of Harvard University chaired the Working Group. She agreed to summarize its deliberations and conclusions for Council, followed by comments from Dr. Murray Goldstein, a Council member who participated in the Working Group. In addition, Dr. Richard Nahin would propose a research concept for NCCAM. Dr. Straus introduced the ad hoc members--Drs. Low Dog, Longhurst, and Weisfeldt. He also mentioned that the FDA has issued a notice in the Federal Register soliciting comments on a proposed rule for ephedra and urged the meeting participants to consider providing comments.
II. Report of the Ephedra Working Group
Dr. Buring summarized the report of the Ephedra Working Group that met on February 26, 2003. She emphasized that the data on the safety of ephedra are not adequate to determine to a degree of statistical certainty that ephedra is either safe or unsafe. They do, however, send a signal of concern. The trials that have been done are too small to lend themselves to a definitive analysis. The adverse event reports, while numerous, lack crucial information, and are insufficiently documented to conclude firmly that ephedra caused them. Of most concern to the Working Group were "sentinel" events that indicated the occurrence of a serious or even fatal adverse event within 24 hours of the subject consuming ephedra while no other causes were identified by autopsy or toxicological analyses. It was clear to the Working Group that additional steps would be necessary to make a firmer determination about ephedra's safety or lack thereof. As to evidence of efficacy, few trials of ephedra for weight loss have been conducted, and there is no evidence regarding the dose-response relationship. For performance enhancement, there have been no clinical trials.
Therefore, in examining possible options, the Working Group suggested a portfolio of research options by which more definitive evidence could be generated. Most importantly, the Working Group made a clear and strong recommendation that NIH, NCCAM, and ODS consider the safety of ephedra as the highest priority.
The Working Group suggested as a first step a case control study to be conducted among adolescents and young adults using ephedra for performance enhancement. While this would be expensive, it would be optimal given the lack of substantial co-morbidity in this group, therefore making it easier to determine any cause-effect relationship with serious adverse events.
The Working Group suggested that other, related activities could be conducted concurrently with the case control study, such as surveys to determine usage patterns, basic research into mechanisms, and clinical trials of a standardized product to evaluate the safety and efficacy of ephedra for weight loss among overweight and obese adults. Clinical trials could include a Phase II study to evaluate adverse effects and other responses, while determining optimal dosages. The next step would be a randomized clinical trial to characterize side effects and to determine efficacy for weight loss. The combination of ephedra and caffeine potentiates the actions of ephedra, so any study will have to consider the combination.
The Working Group was not asked to address the regulation of ephedra, but the members volunteered that they felt the situation was analogous to that of a new active drug. While resources are limited, the safety issue is an overarching priority. Investing research dollars in establishing efficacy for weight loss was not seen as having as high a priority at present.
One Council member asked why there was no mention of other clinical uses for ephedra, such as treatment of congestion or asthma. Dr. Buring explained that while the Working Group relied on the RAND report, which looked at performance enhancement and weight loss, they were very aware that ephedra is used for other purposes. Dr. Paul Coates, ODS, noted that there is very little literature on ephedra for purposes other than weight loss, despite its traditional uses.
There was discussion about getting meaningful industry sales data that would indicate the volume of ephedra sold. There is some difficulty with that, because many different products are sold, and ephedra is seldom sold as a single agent.
Dr. Straus asked Dr. Goldstein as the Council liaison to the Working Group to comment. Dr. Goldstein thanked the review committee for the very hard work of examining a great deal of data. He noted that the Council faced certain policy issues alluded to in the report. Addressing the Council, he said that given the public health significance of sentinel events, and recognizing recent public alarm, there was a need to face the issue of whether initiating a study should be a priority for research support. He asked that they consider the question of priority from a scientific and public health standpoint.
Dr. Straus asked the Council to discuss whether studies of ephedra should be a priority for NCCAM. Dr. Low Dog said that NCCAM should be involved in looking at safety. She is concerned about adolescents and young adults. While labels on these products specify that they are not to be used by people under 18, it was noted that the youngest fatality in the RAND report was a 13-year-old.
Studying a young, healthy group will give different answers than will examining an older, less healthy group that might be more concerned with weight loss.
Dr. Timmerman said that she supported a safety study, and that NCCAM is the right place for this research. Dr. Weisfeldt thought that this is a very important issue that is not limited to young people. If ephedra were brought out as a drug today from scratch, they would start with a Phase I study, then Phases II and III, followed by a Phase IV to observe use and safety in the community setting. The Working Group indicated that it would be unethical to conduct prospective Phase II and III studies for the express purpose of triggering life-threatening adverse reactions. Dr. Weisfeldt wondered if they should conduct a Phase I trial and investigate heart rhythm irregularities.
Dr. Goldstein asked that the Council recommend approval of an NCCAM announcement soliciting proposals for study of the safety of ephedra. Council concurred in principle.
Dr. Goldstein's second point concerned a well-designed and approved study, which could be fairly expensive. Therefore, even though NCCAM is the focal point at NIH for studies of this sort, the public health impact of ephedra use extends to other NIH organizations. This is clearly a multi-institute activity. Therefore, he proposed that the Council strongly recommend that Dr. Straus interact with other institutes and solicit collaborations, especially financial collaboration. No Council member disagreed with this statement.
Dr. Goldstein's third point was that there are other research questions about ephedra. In addition to a targeted initiative addressing ephedra safety, a program announcement with no set-aside funds could be issued to encourage the scientific community to submit proposals.
III. Concept Review
Based on the conclusions of the Ephedra Working Group, Dr. Nahin developed and presented a concept for the Council's consideration, a Case-Control Study to Investigate the Safety of Ephedra. Dr. Nahin explained that in the proposed prospective case-control study, investigators would identify the cases--stroke, heart attack, etc.--presenting to emergency departments. Investigators would send a team into the homes of the participants to identify any dietary supplements used. The investigators would take these supplements, analyze them, and put their use in context with any other medications and/or supplements the subject was taking.
The Working Group had decided that the main question concerned the safety of ephedra, but had debated the precise target study population. The inclusion of older individuals with severe co-morbidities including morbid obesity would confound the ability of the study to yield a clear result. The control group would have to include an equivalent population, which would make the results less sharp.
Another concern is that adverse events in populations with existent disease, such as hypertension, would be less likely to be linked to use of the supplement. On the other hand, for a healthy young population, emergency room visits for infarcts and strokes would be unexpected and, therefore, noticed and investigated.
Dr. Buring explained that the Working Group had struggled with these issues. With unlimited resources, ephedra use by the young desiring performance enhancement, and by young to middle-aged obese populations could both be studied. However, since resources are limited, they thought it best to study the young. The Working Group considered many issues that might impact on the study. First, they discussed the emotional overtones of people wanting to protect this age group. Second, are the issues of risks and benefits. Nothing is completely safe, but the risk/benefit ratio among the young is different from that of the middle aged. If there is no efficacy, then the safety concerns are amplified. Third, when dealing with the obese population, there are other factors such as hypertension that are not easy to separate from ephedra effects. Therefore, the first study should be in younger adults. A Phase I study would provide information about the effects quickly, and determine how ephedra might work. However, this would not answer the safety question. Therefore, the Working Group decided that the proposed study would answer the questions people are asking.
Dr. Nahin explained that NCCAM intends to collaborate with other institutes on this, as it is an issue that is relevant to many ICs. The funding mechanism proposed for the concept is the U01 cooperative agreement, in which NCCAM staff, IC partners, and the investigators would work as co-investigators; cooperative agreements require much staff involvement. It was estimated that a prospective case control study could take four to eight years, at a cost of $2-4 million per year, for a total upwards of $16 million.
IV. Discussion
Dr. Straus revisited the issue about duration and dollars. He asked if members of Council thought it appropriate to have ephedra research as a high priority, given the cost estimates provided by Dr. Nahin. One Council member suggested conducting a Phase I study first, expressing concerns about having to go into people's homes, which is a huge task, and wondering how they would also evaluate what other substances subjects might be taking. Dr. Nahin said that if a Phase I study identified toxicities, there would remain a need to do Phase II and III studies to get sufficient data to be certain about ephedra safety and efficacy. However, since the suspected SAEs are rare, thousands to tens of thousands of participants would be needed.
There was debate about prioritizing a multi-year, multi-million dollar trial compared with other studies brought to Council. However, there was agreement that the public health importance of this issue necessitated some response. One person noted that it makes sense to undertake this as a high priority in that context, given NCCAM's role in the NIH and public health communities.
Issues related to spiking of the products with synthetic chemicals, use of different cultivars by different suppliers, various combinations of products on the market, and high intake in the United States of caffeine in other dietary products were identified as potential problems that could confound an ability to conclude that it was ephedra and not other constituents in supplements that predispose to SAEs.
V. Public Comment
Dr. Hathcock of the Council for Responsible Nutrition said that the relative risk issue for ephedra had been raised earlier, but he referred to data that shows the actual risk is lower. In his opinion, the RAND report had some methodological shortcomings: it leaves out information about the mid range dose, it fails to discuss ephedrine and caffeine, it does a poor job with the meta-analysis, it omits the nutritional effects, and it extrapolated from ephedrine to ephedra for weight loss but not for athletic performance. The FDA has issued a notice soliciting comments for rulemaking, which would provide a range of options. Legislative proposals, insurance issues, and publicity are active right now. He noted that dosage information is often not reported correctly.
Dr. Dentali of the American Herbal Products Association commented that the association has recommended stating contraindications to ephedra use on the label since before Dietary Supplement Health and Education Act of 1994 (DSHEA). Product quality is an issue; he urged NCCAM to avoid products with pseudoephedrine. The most common use of ephedra is for obesity. Performance claims are not currently allowed. If ephedra disappears from the marketplace, there is no point to further study it if the only target population is people who use ephedra for performance enhancement.
VI. Discussion, continued
Based on the Working Group's recommendations and the extended discussions at Council, Dr. Nahin refined his proposed concept to be a prospective case-control safety study in persons aged 18 to 40 or more who chose to use ephedra for any purpose. Although the Working Group had suggested an upper age limit of 30, this might exclude many adult women who take weight loss products. The reason to extend the study to people who use it for any purpose and not just performance enhancement, as originally suggested by the Group, was that weight loss is a more important health goal than performance enhancement.
Dr. Straus said that the FDA is calling for comments regarding options to further regulate sales of ephedra as a dietary supplement. If ephedra leaves the market, the question of its safety is almost moot and a prospective case-control safety study could not be done. Other kinds of ephedra studies, such a study of its value for weight loss, might then be a priority. However, ephedra is on the market today, and people are taking these products. The real question is whether the products people are taking are dangerous or not. Dr. Straus said that the bar to prove scientifically that something is unsafe is very high.
Dr. Straus called for a vote on the concept. Of the voting Council members, 7 were in favor of the concept of an ephedra case control study; 3 were against it, feeling that NCCAM should not expend its resources pursuing the toxicity of ephedra.
Dr. Coates commented that from the perspective of ODS, development of an ephedra research approach, including the design and support of the RAND study and the Working Group, represented a close and effective partnership with NCCAM from the beginning. He and Dr. Straus had planned and worked toward development of a research agenda for ephedra for a long time. Further studies of ephedra under the leadership of NCCAM and ODS will need to include other Institutes, Centers, and Offices at NIH.
VII. Adjournment
Dr. Straus adjourned the meeting at 4:05 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
