Note: The entire meeting was open to the public. Copies of written information provided to the Committee for consideration are available from the Committee Staff. This includes written materials received from public participants. A transcript of this meeting is available from the FDA Dockets Management Branch (HFA-305), 12420 Parklawn Drive, Rockville, MD 20857.
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Special Working Group members present: Dr. Edward N. Brandt, Jr. (Chair, Special Working Group and Food Advisory Committee), Dr. Lester M. Crawford (Vice Chair, Special Working Group), Dr. George L. Blackburn, Dr. Henry W. Blackburn, Dr. Edward M. Croom, Dr. Steven Dentali, Dr. Stephen P. Glasser, Dr. Donald R. Jasinski, Dr. George Ricaurte, Ms. Donna Richardson, Dr. Andrew L. Stoll, Dr. Varro E. Tyler, and Dr. Mary Y. Wang.
Special Working Group members absent: None
Special Industry Liaisons: Mr. Michael Ford, National Nutritional Foods Association, and Mr. Loren Israelsen, Utah Natural Products Alliance.
Members of the Food Advisory Committee in attendance as observers: Dr. Stephen H. Benedict, Mr. John H. Guzewich, Dr. Dennis Hsieh, and Dr. Morris Potter.
Guest Expert: Mr. Steve Lee, Weider Nutrition Group
Food and Drug Administration (FDA) representatives: (Center for Food Safety and Applied Nutrition - CFSAN) Dr. Lynn A. Larsen, Executive Secretary of the Food Advisory Committee; Dr. Fred Shank, Center Director; Ms. Catherine DeRoever, Ms. Linda Hayden, and Ms. Joyce Perticone, Committee Staff; Dr. Joseph Betz, Ms. Constance Hardy, Dr. Lori A. Love, Dr. Elizabeth Yetley.
Guest Speakers: Ms. Cynthia T. Culmo, Texas Department of Health; Dr. Richard Ko, California Department of Health Services; and Dr. F. Xavier Pi-Sunyer, St. Luke's/Roosevelt Hospital, New York, NY.
Public Speakers: Dr. Dennis Jones, President, Fytoresearch Inc.; Mr. Anthony Young, Piper & Marbury, on behalf of the National Nutritional Foods Association; Dr. Dennis Baker, Texas Department of Health, on behalf of the Association of Food and Drug Officials (AFDO); Mr. David Litell, Chemin Co.; Mr. Michael McGuffin, American Herbal Products Association; Dr. Calvin McCauseland, Enrich International; Mr. Stephen Shapiro, Bass & Ullman, on behalf of Starlight International; Ms. Diana Kaye, on behalf of herself and the Alliance for Non-Toxic Living and Environmental Responsibility (ANTLER); Mr. Michael Scott, Scientific Toxicology and Technology (ST&T); Mr. Clinton Miller, National Council for Improved Health, presented comments prepared by Dr. Alvin Segelman, Vice President of Health Science, Nature's Sunshine Products; Mr. Adam Gissen, Vitamin Research Products; Mr. Michael Betz, Omnutrition; Mr. William Appler, Executive Director, Ad Hoc Committee on the Safety of Ma huang.
Agenda:
Dr. Brandt, Chairman of the Special Working Group, convened the meeting at 9:00 a.m. Wednesday, October 11, 1995. The issue before the Special Working Group was the potential public health problems associated with dietary supplements and other food products containing botanical ingredients that are sources of ephedrine alkaloids. The agenda for the first day included presentations by CFSAN staff on the sources of concern (adverse event reports and scientific literature), on the chemistry of the plants used, and on an FDA review of products in the marketplace. Three guest speakers followed the initial CFSAN presentations. The guests spoke on the traditional use of botanical materials in Chinese herbal medicine; on experience in the State of Texas with adverse events associated with foods, dietary supplements and drugs containing ephedrine alkaloids; and on the consequences of rapid weight loss. A final CFSAN presentation detailed the adverse events reported to the Agency, and summarized the scientific and clinical literature on expected reactions from consumption or administration of ephedrine alkaloids. Time being available, an additional opportunity for an open public hearing was offered. The meeting recessed at 3:30 p.m.
The meeting reconvened the next morning at 9:00 a.m. After the scheduled open public hearing was held, the Special Working Group was reminded of its charge and proceeded to develop its responses to the questions posed by FDA. The Special Working Group adjourned at 1:00 p.m., Thursday, October 12, 1995.
Presentations - FDA
Dr. Yetley introduced the issue to the Special Working Group. She explained that while the substances of concern occur in both food and drug products, the issue before the Group was not the regulatory category, but rather the potential public health problems when the substances are in products FDA considers to be foods. She provided an overview of the adverse event reports that led to FDA's concern, and described the topics to be presented by other speakers.
Dr. Betz briefly detailed the chemical structures of several ephedrine alkaloids, and described the botanical sources, the plant parts used, the particular ephedrine alkaloids in each, and the history of use. Among the 45 different species of Ephedra, four are considered to be "Ma huang" as used in commerce. He concluded his presentation with a discussion of the analytical methods that have been used to qualitatively and quantitatively determine the presence of the various ephedrine alkaloids. He described the advantages and disadvantages of each, and provided details of the particular methods selected for use in the FDA market review.
Ms. Hardy described FDA's market review of products. She noted that the review primarily included those products marketed on the East Coast or by mail order. She summarized the analytical data obtained for the various ephedrine alkaloids, and for xanthine alkaloids when they were also present. The content of ephedrine alkaloids ranged from "not detected" to 110 mg/recommended serving. Ms. Hardy also described the variety of label statements appearing on the products, noting in particular that some products bore labeling statements (use indications, warnings, recommendations, etc.) that were in direct contradiction with statements on other products.
Dr. Love provided the Working Group with an extensive, detailed description of the adverse events reported to the Agency. She noted the shortcomings of a voluntary reporting system, and the consequent uncertainties in associating adverse events with a particular cause. However, she stressed the importance of voluntary reporting systems and the common threads running through the reports. Some commonalities were: the nature and severity of the adverse events; the timing of onset; the similarity of signs and symptoms reported with these products to both the known physiological effects of ephedrine alkaloids and with effects noted in clinical trials of ephedrine; and the high percentages of specific types of adverse events, among all those contained in the reporting system, that were clustered among products containing herbal sources of ephedrine alkaloids. There were three main groupings of adverse events: cardiovascular (e.g., tachycardia, hypertension, dysrhythmias, strokes, myocardial infarction), central nervous system (e.g., anxiety, nervousness, insomnia, psychosis, seizures), and other (e.g., nausea, diarrhea, hepatitis, dermatitis, numbness, dizziness, weakness).
Guest Speaker Presentations
Dr. Ko provided a highly informative, succinct presentation on the nature and practice of traditional Chinese medicine. He indicated that, typically, such medications were always provided as a compounded remedy with several other herbs, that patients were given detailed instructions on preparation and use, and that the remedy was prescribed for very specific indications. He noted that Ma huang was not used as a food product, and that uses did not include many of those for which the products of concern currently are being promoted (e.g., weight loss and energy). Specifically, traditional use of Ma huang is for such ailments as the common cold, fever, and asthma. Consumption is typically as an herbal infusion (tea). Dosage is controlled by the practitioner's knowledge of the herbal source, compounding, and use instructions.
Ms. Culmo summarized the adverse events reported in Texas associated with food and OTC drug products containing ephedrine alkaloids, including multiple adverse event reports for one particular product that contained, at the time, both a source of ephedrine alkaloids and a source of xanthine alkaloids (caffeine in particular). After evaluating the nature and number of adverse events, the State took action to remove the product, as formulated, from the market.
Dr. Pi-Sunyer provided a graphic presentation of the potential problems associated with rapid weight loss. He particularly noted the potential for adverse loss of protein and muscle mass when body weight is near ideal body weight, whether at the start of a weight-loss regimen (among those who are trying to be slimmer) or near the end of a weight-loss program for an initially obese individual. The potentially negative impact on cardiac muscle, liver and skeletal muscle was noted. Other adverse consequences of rapid weight loss that were identified included gall bladder inflammation and gallstones.
Public Hearing Presentations
Most of the speakers in the two open public hearing sessions represented firms or trade groups in the herbal products or dietary supplement industries. They urged continued but responsible use of Ma huang and related herbal materials. They based their views of safety on analyses of studies compiled from a search of the literature, and in particular a safety review performed by the Ad Hoc Committee on the Safety of Ma huang. The speakers disassociated themselves from the use of synthetic ephedrine, declaring this to be a drug use and adulteration of dietary supplements and food products. Several speakers supported the concept of limits on ephedrine alkaloid content in dietary supplement and food products, and of appropriate labeling with respect to use instructions and cautions about contraindications. Ms. Kaye pleaded for continued availability of such products because of their vital need by chemically-sensitive asthmatics. Dr. Baker indicated that AFDO had passed a resolution in June, 1995, recommending removal of ephedrine products - natural and synthetic - from foods, dietary supplements and over-the-counter (OTC) drugs. He noted that the drug and food products were promoted for the same uses, and that 26 States had taken some action against ephedrine alkaloid-containing products.
The Chair, during the course of the meeting, also granted requests from two of the Food Advisory Committee members observing the meeting to make brief comments. Dr. Dennis Hsieh acknowledged his ethnic heritage and his use of traditional Chinese medicine. He strongly emphasized the traditional indications and conditions of use of Ma huang, and how these differed from the uses being promoted for the products in question. Mr. Guzewich wondered whether there were adverse event reports from other countries. Dr. Love replied that FDA has heard of similar problems elsewhere, but that the Agency had not received official reports on these adverse events.
Special Working Group Discussion and Conclusions
Throughout the course of the meeting the Special Working Group members entered into often extensive discussion with the various speakers. The breadth and depth of expertise on the panel also led at time to extensive internal debate of the issues.
Some members of the working group expressed skepticism about the conclusions that could be drawn from a voluntary adverse event reporting system, particularly in light of the frequent confounding factors. Other members were struck by the correlation between adverse events in the reported cases and those in clinical studies of pharmaceutical ephedrine. While most members appeared to agree that ephedrine should act the same chemically, regardless of source (natural or synthetic), there was less agreement about the impact of matrix (i.e., the material accompanying and containing the substance) on pharmacologic activity at the sites of action in the body. Consequently, there was much debate about what indications and contraindications should be included in the labeling of these products.
There was significant debate about the safety (and value) of permitting these products to remain on the market as dietary supplements and food products. The consensus, with continuing reservation harbored by some members, was that there were conditions, relating to content, labeling and manufacturing, under which products containing botanical sources of ephedrine alkaloids could continue to be made available to consumers as foods and dietary supplements. The discussion of content focussed on limitations of exposure per "serving" (i.e., "dosage" limits); the labeling discussion focussed on conditions for use (including warnings on duration of use). Several members also proposed that conditions of good manufacturing practice be applied. It was suggested that these should include standardization of the quality of the botanical material and of the quantity (both in terms of total alkaloids and total ephedrine alkaloids), as well as proper botanical identification on the label.
Discussion of the various viewpoints on the issues continued as the panel began to address the questions posed by FDA. Agreement appeared to be reached on most questions. A copy of the focus, charge and questions is attached to these minutes. The summary paragraphs below are labeled as the questions were presented to the Working Group.
1.a. The first question sought the working group's opinion on the association of the adverse events reported with the use of ephedrine alkaloids. A summary listing of adverse events reported to FDA was provided. The working group recognized and understood the inadequacies inherent in a voluntary adverse event reporting system. Taking that into account, however, there was group agreement that there may be an association between the types of serious events reported and the use of ephedrine alkaloids.
1.b. The second question posed to the Group related to all the information FDA considered in drawing its tentative decision that food products containing ephedrine alkaloids may cause serious adverse events. The working group was asked if this information was appropriate and sufficient for FDA to draw its conclusions. There was significant debate on this question. One member noted that the epidemiological data on use and abuse were inadequate. Another member expressed concern about the absence of clinical trial data on ephedrine-containing foods. After much discussion, however, the panel reached consensus that, if adjustments are made so the evaluation takes dose, duration and sensitivity into account, the information is appropriate and sufficient.
1.c. The panel was provided with a list of criteria used by FDA tentatively to conclude that certain foods containing ephedrine alkaloids may cause serious adverse events. The third question asked of the Group was whether these criteria were appropriate and sufficient to lead FDA to its tentative conclusion. The ensuing extensive debate focussed primarily on whether or not there was a consistency in the data, and FDA's use of the word "consistency." FDA opined that there was a consistency of illnesses/injuries across the reported adverse event reports, a consistency of types and patterns of illnesses/injuries reported for foods with those for related OTC drug products, a consistency of illnesses/injuries reported for foods with the effects of ephedrine alkaloids in clinical trials and medical and scientific literature, and a consistency of illnesses/injuries reported for food products and known pharmacological/toxicological effects of ephedrine alkaloids. Some members felt that there was a pattern, and there was "consistency." Others felt that the word "consistency" was not an appropriate description, but suggested that they might agree if "similar" or "similarity" were used. The conclusion of the Chair was that the group had come to a somewhat tentative consensus, provided there was considerable leeway in interpretation of the words used to describe the relationship between the illnesses/injuries reported and the other factors that were evaluated.
2.a. The panel felt that its earlier discussions had already provided the answer to this question, which asked about agreement with FDA that the use of certain foods containing ephedrine alkaloids may cause serious adverse events. The answer was, yes, particularly when sensitivities, behavior, genetics, dose and duration are taken into account.
2.b. Working group members agreed that the use of ephedrine alkaloids in food products is not unsafe under all conditions of use. Although some were concerned about the presence of ephedrine alkaloids near or at OTC drug levels, as a group there was consensus that conditions of safe use could be identified. Among the conditions discussed were appropriate labeling for conditions of use and contraindications (including use no more than seven days), establishment of a single dose limit and daily use limit of ephedrine alkaloids contained in dietary supplements and other foods, and production of the foods and dietary supplement products under prescribed good manufacturing practices (including standardization of the level of naturally occurring ephedrine alkaloids in each product unit).
2.c The discussion about the issue of quantity of ephedrine alkaloids narrowed the question to focus on safe use of such substances in dietary supplements under indicated conditions of use by most consumers. There was concern about lack of adequate data to establish "dose" or serving limitations. One suggestion proposed was a per-unit limitation of 20 mg ephedrine (25 mg total ephedrine alkaloids), with a daily intake of no more than 80 mg ephedrine (100 mg total ephedrine alkaloids), consistent with current maximum OTC drug levels. However, a wide range of lower levels per unit were also discussed. The Group suggested that FDA begin its consideration at some level below that currently used in OTC drugs. There was consensus that use instructions should advise consumers that using more of the product, or more frequent use of the product, than instructed does not guarantee or increase effectiveness.
2.d. The Working Group could come to no consensus on products containing both ephedrine alkaloids and other materials that might act to increase the likelihood or severity of adverse events (e.g., caffeine or caffeine-containing materials). Some members felt there was inadequate scientific data to draw firm conclusions, but yet they believed that mixing ephedrine alkaloids and stimulant materials may not be a healthful practice. It was suggested that if other stimulants are present, they should be declared on the label, along with their source material, e.g., caffeine from cola nut.
2.e. The Group consensus was that the form used in food and dietary supplements must be the botanical or a suitable derivative thereof (i.e., an extract). The issue of prescribing good manufacturing practice was again raised, particularly with respect to extracts. Standards need to be established for methods of preparing extracts, and in particular there is a need to identify clearly and to validate the level of concentration attained. For all products, the levels of ephedrine and ephedrine alkaloids need to be evaluated against an appropriate standard and validated for each lot. There also was strong agreement that there must be more laboratory and clinical research on the safety and use of a wide variety of herbal materials, including Ma huang.
2.f. There was extensive discussion about the need for and the nature of labeling statements. There was consensus that detailed and specific labeling was needed to protect consumers from potential illness and injury through misuse or abuse of appropriately manufactured dietary supplement products containing ephedrine alkaloids. During Group discussion, it was suggested that this degree of labeling not be extended to the "crude" (i.e., unprocessed) herb itself, such as might be found in a Chinese herbalist's shop. Among the use and cautionary statements that the Group felt should be included in labeling were:
A statement discouraging consumption of more than the recommended amount or more frequently than recommended, because of the potential for illness or injury at higher or chronic intake (e.g., cardiovascular, neurological or psychiatric reactions).
Use instructions, including safe duration of use and maximum safe intake ("dose") and that taking more does not increase the benefit or effectiveness.
A statement noting that the product is not intended for use by persons under 18 years of age.
A caution against consumption if a consumer is pregnant, is taking certain drugs, or has certain diseases or psychiatric disorders.
A statement that the product is intended to be used as a dietary supplement.
Identification of any other stimulants present, and their sources
Amount of ephedrine alkaloids contained in the product
Edward N. Brandt, Jr.
Chair, Food Advisory Committee
and Chair, Special Working Group on
Food Products Containing
Ephedrine Alkaloids
Lynn A. Larson,
Executive Secretary
Food Advisory Committee
ATTACHMENT
Minutes of the Special Working Group on Food Products Containing Ephedrine Alkaloids
Executive Secretary's Note: The following four pages contain the charge and questions as they were provided to the Working Group members. The transcript and minutes reflect Working Group discussion about the wording of some of the questions and lead-in statements. For example, appropriateness of the word "consistency" as used by FDA in statements preceding question 1.c. was discussed. Please note, in particular, that question 2.c. was narrowed by the Working Group form dealing with "...food products...used under comrnon conditions of use..." to addressing "...dietary supplements...used under indicated conditions of use..."
CHARGE & QUESTlONS POSED TO THE WORKING GROUP
Focus
This Working Group of the Food Advisory Committee is being asked to consider the safety of food products containing a source of ephedrine alkaloids, including ephedrine, pseudoephedrine, and norpseudoephedrine from Ephedra sinica Stapf. (also called Ma huang and Chinese ephedra) and other related species,l whose use is associated with reports of serious adverse events.
The focus of the Working Group is on the significance and extent of the serious adverse events associated with the use of food products containing a source of ephedrine alkaloids, and on the strength of the science and data associating the foods with the events.
The focus is not on whether the products are foods or drugs, or whether the products have documented effectiveness for any labeled function.
Charge to the Special Working Group
The Working Group is being asked to consider whether food products containing ephedrine alkaloids, whose use has been associated with serious adverse events--such as paranoid psychosis, hypertension, convulsions, stroke, cardiac dysrhythmia (i.e., abnormal heart rhythm), myocardial infarction (i.e., heart attack), stroke, coma and death, pose a significant health concern to the general population or to subgroups of the general population, such that some action by the Food and Drug Administration (FDA) to protect the public health is appropriate.
Questions
1. FDA has tentatively concluded that there is an association between the use of certain food products containing ephedrine alkaloids and serious adverse events. The serious adverse events, including those that have resulted in death, associated with the consumption of ephedrine alkaloids generally include:
Cardiovascular (i.e., heart and blood vessels): hypertension, palpitations, dysrhythmias, cardiac arrest, chest pain, myocardial infarction, stroke;
' Other species include: E. equisetina Bge., E. intermedia Schrenk et C.A. Mey., E. gerardiana Wall et Stapf. (Pakistani Ephedra)
Central nervous system (i.e., brain and spinal cord): anxiety, nervousness, tremor, hyperactivity, insomnia, behavior and memory changes, psychosis, suicidal, altered or loss of consciousness, disorientation, confusion, seizures;
Other:
Dermatologic (e.g., dermatitis);
Gastrointestinal (e.g., gastrointestinal distress, hepatitis and altered serum enzymes);
Genitourinary;
Hematopoietic;
General (e.g., numbness, tingling, dizziness, fatigue, lethargy, weakness, headache, edema and rash).
a. Do you agree that these types of serious adverse events are associated with the use of ephedrine alkaloids?
FDA's tentative conclusion that use of certain food products containing ephedrine alkaloids may cause serious adverse events is based on the following:
a review of the adverse event reports for food products containing ephedrine alkaloids;
a review of the adverse event reports for over-the-counter (OTC) drug products containing ephedrine compared to the types and patterns of adverse events with food products containing a source of ephedrine alkaloids;
a review of the scientific and medical literature on the use, misuse and abuse of products containing ephedrine alkaloids, including the effects of ephedrine alkaloids documented in clinical trials;
a review of the literature on the known pharmacological and toxicological effects of ephedrine alkaloids; and
to the best of FDA's knowledge, the absence of scientific data demonstrating that ephedrine alkaloids from different sources differ in their safety (e.g., botanical versus synthetic).
b. Do you believe that the above information is appropriate and sufficient to enable FDA to draw a conclusion that certain foods containing ephedrine alkaloids may cause serious adverse events?
The following criteria were used to evaluate the available data, which serve as the basis of FDA's tentative conclusion:
consistency of the reported illnesses and injuries across the wide variety of adverse event reports involving diverse food products containing ephedrine alkaloids;
consistency of the types and patterns of illnesses and injuries reported for food products containing ephedrine alkaloids and those reported in adverse event reports for OTC drug products containing ephedrine;
consistency of illnesses and injuries reported for food products containing ephedrine alkaloids with reported effects of ephedrine alkaloids from clinical trials;
consistency of the illnesses and injuries reported for food products with reports in the medical and scientific literature on the effects of use, misuse and abuse of products containing ephedrine alkaloids;
consistency of the illnesses and injuries reported for food products with the known pharmacological and toxicological effects of ephedrine alkaloids;
and the label information and the quantity of ephedrine alkaloids in the market review of products containing ephedrine alkaloids (see Market Review at Tab H).
c. Do you believe that the above criteria provide appropriate and sufficient information for FDA to conclude that certain foods containing ephedrine alkaloids may cause serious adverse events?
2. Based on what you have heard at this meeting, and on your expertise, knowledge and experience and considering:
the totality of the available data and information;
the criteria for evaluating the available data and information;
the likelihood of some individuals being sensitive to low levels of ephedrine alkaloids; and
the examples of products available in the marketplace (see Market Review at Tab H):
(1) range of products containing ephedrine alkaloids and the amount they contain;
(2) label directions for use;
(3) other substances in these products or other foods consumed simultaneously with the food products containing the ephedrine alkaloids.
This meeting was held in October 1995.
For more recent information on Dietary Supplements
See
http://www.cfsan.fda.gov/~dms/supplmnt.html
Hypertext updated by ear/dms/kwg 2000-NOV-16