December 20, 2000

Docket Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852

fdadockets@oc.fda.gov

Docket No. 00N-1200 -- Ephedra

The Council for Responsible Nutrition (CRN) is submitting this comment in response to the Federal Register notice dated July 31, 2000 (65 FR 46721) that extended the deadline for comment to this docket to September 30. This new comment closing represented a second extension, first from May 18 to July 3, and then from July 3 to September 30.

On June 13, CRN’s John Cordaro wrote Mr. Joseph Levitt, Director of the Center for Food Safety and Applied Nutrition at the Food and Drug Administration (FDA), requesting a further extension of the comment deadline for two major reasons: (1) potentially pivotal new data on ephedra were scheduled to be released within a few months by researchers at Columbia and Harvard universities, and (2) a CRN-sponsored quantitative risk assessment by Cantox Health Sciences International (Cantox risk assessment) was under way and would be completed soon after the Columbia/Harvard data became available. At that time, CRN stated that it would be premature for either FDA or CRN to reach scientific conclusions on the safety of ephedra without waiting for the Columbia/Harvard data and the Cantox risk assessment. CRN argued that some delay was reasonable, especially in light of the several years that the FDA has been reviewing the safety and appropriate regulatory policy on ephedra. It has been over three years since FDA issued its proposed rule on ephedra.

On September 13, Mr. Levitt denied CRN’s request to extend the deadline. On September 27, CRN commented to this docket, explaining that it would submit the final report from Cantox when it was completed. CRN also noted the strong potential of the Columbia/Harvard clinical trial to have a major impact on the total evidence, and therefore, the risk assessment would be completed only after those results became available.

On November 1, 2000, at the annual conference of the North American Association for the Study of Obesity, the Columbia/Harvard researchers (Drs. Carol Boozer, Patricia Daly and colleagues) released a detailed abstract of the results of their randomized, double-blinded, placebo-controlled clinical trial. This abstract is publicly available and is scheduled to be published by Boozer et al. in the January 2001 issue of Obesity Research. Details of the protocol and methods were discussed by Dr. Daly at the August 8 and 9 Department of Health and Human Services public conference on ephedra and are part of the public record of that conference.

On November 1, 2000, CRN transmitted the Columbia/Harvard abstract to Cantox and asked Cantox to proceed with finalization of the quantitative risk assessment on ephedra. The final report is being submitted to FDA today.

CRN’s Synopsis of the Cantox Health Sciences International Quantitative Risk Assessment on Ephedra Used as a Dietary Supplement

Introduction

Cantox Health Sciences International, based primarily in Canada, provides scientific consulting services, specializing in safety and regulatory issues related to products and processes as they affect human health and the environment. For the past 20 years, Cantox has worked with clients and projects in 108 countries on six continents. Cantox’s President, Ian Munro, Ph.D., is a world renowned regulatory toxicologist and is Chairman of the UL Subcommittee, Food and Nutrition Board, U.S. National Academies. Cantox’s principal investigator on the ephedra risk assessment project was Earle Nestmann, Ph.D., a Cantox Principal, who is a recognized authority in toxicology with extensive experience in regulatory issues and risk assessment. The ephedra risk assessment was contracted by CRN and funding was provided from CRN operating funds, not uniquely from members with a special interest in ephedra.

Objective

The objective was to perform a quantitative risk assessment for the botanical ephedra as used in dietary supplements, which involved a review and interpretation of all data sources and determination of an Upper Limit (UL) for ephedrine alkaloids in ephedra. This was done through application of the Tolerable Upper Intake Level (also called Upper Limit, or UL) method developed by the Food and Nutrition Board (FNB), Institute of Medicine, National Academies for application to nutrients. In accordance with this risk assessment model, benefits were not reviewed and no risk-benefit analysis was performed.

Data Reviewed

The data on both ephedra and ephedrine were reviewed. Since ephedra contains other ephedrine-type alkaloids that are less biologically active than ephedrine, the use of ephedrine as a surrogate for ephedra produces a conservative risk assessment. The ephedra/ephedrine data assessed included animal toxicology (including two lifetime studies on mice and rats) and pharmacokinetics, human pharmacokinetics, 19 clinical trials directly pertinent to the safety of ephedra, adverse event reports (AERs) released by FDA, published case reports, and review articles.

UL Method Advantages

The UL method was developed by the UL Subcommittee of FNB’s Dietary Reference Intakes Committee, and thus, represents an authoritative perspective on risk assessment. The UL method uses an objective approach and criteria established in advance of performing a risk assessment, thus avoiding reviewer bias about the process. The method is designed for application to deliberate ingredients with intended biological effects such as nutrients, rather than impurities, contaminants, or food additives with no intended biological effects. All data sources are evaluated, and reliance is placed on the strongest type of data available as well as coherence of the reliable sources of data. The UL method incorporates and demands application of a systematic set of criteria for causality that are identified in advance. Finally, the UL method employs uncertainty factors (UFs) that are fully derived from specific databases, thus avoiding arbitrary factors.

Findings

Based on the totality of evidence from all types of evidence, the No Observed Adverse Effect Level (NOAEL) for ephedra is 90 mg/day (as 3 x 30 mg). The Lowest Observed Adverse Effect Level (LOAEL) is 150 mg/day, but the adverse effects at this level are of moderate intensity and are not life-threatening or debilitating. Using the database that provided the NOAEL, the UF is 1.0. Therefore, the UL is 90 mg/day, under specified conditions of use, with the intake split into at least 3 servings of no more than 30 mg to be taken at one time.

Basis of Conclusions

The UL is derived from the totality of the evidence, particularly the results of 19 relevant clinical trials, including that of Boozer et al., 2000. The data of Boozer et al relating to intakes of 90 mg/day of ephedrine alkaloids from ephedra are consistent with and supported by several other clinical trials at somewhat lower intakes (60 to 75 mg/day) of ephedrine or ephedrine alkaloids from ephedra. The Boozer et al. clinical trial has a very strong protocol design that provided 90 mg/day of ephedrine alkaloids from ephedra, plus 192 mg of caffeine from kola nut. The trial monitored numerous safety parameters, and no adverse effects were observed. The only effects observed other than the beneficial effect of weight loss, were those expected from intake of stimulants (e.g. insomnia and modest increases in heart rate), and none were classified as adverse.

The AERs are not conclusive and, therefore, are not an adequate basis for identifying appropriate limits. Most of the reports focused on the product identity and characterization of the adverse event. Many contain little information of reliable quality. Others lack critical information needed for any possible assignment of causality. Reliable dosage information is missing from most. Some are confounded by preexisting conditions and others by concomitant intakes of other substances that may have caused or contributed to the adverse effect. The overall rate of adverse effects is low, considering the amount of ephedra sold and consumed.

With FDA’s recent public health warning on phenylpropanolamine (PPA) and the potential for public confusion about the applicability of this warning to ephedra dietary supplements, this issue is addressed directly. The content of the daily amount of ephedra administered in the clinical trial by Boozer et al is less than 1.8 mg. The ephedrine content is 60 mg or less. If one assumes the maximum reported metabolic conversion to PPA (20 percent), the daily exposure to PPA would be less than 14 mg. The FDA Nonprescription Drug Advisory Committee, at its October 19, 2000 public meeting, found no significant risk from PPA intakes less than 75 mg per day. Thus, the maximum exposure to PPA from use of ephedra with 90 mg of alkaloids is far below the apparent PPA threshold of 75 mg per day.

The literature survey revealed no overriding concerns of adverse events based on animal pharmacokinetic and toxicology studies or investigations of human pharmacokinetics.

Conditions for Safe Use of Ephedra Supplements

Based on the scientific evidence, the conditions for safe use of ephedra dietary supplements specified in the Cantox report include:

1. Dosage limits of 90 mg per day, with no more than 30 mg per dose.
2. Labeling to provide exclusions and contraindications consistent with the 19 clinical trials that are the basis of the UL.
1. Contraindicated for some persons
2. Check with healthcare provider about use
3. Limit use to 6 months or less
4. Not for any less than 18 years old
3. Post-market monitoring.

Caffeine (192 mg/day) was included in the Boozer et al. clinical trial test material, and caffeine sources such as coffee were not eliminated from the subjects’ diets. Combination ephedrine and caffeine products were the test materials in several of the other clinical trials. Thus, similar intakes of caffeine are not contraindicated for persons taking ephedra.

Summary of Cantox’s Risk Assessment of Ephedra

Risk assessment is an established and reliable tool for identifying limits for food ingredients. The UL method was developed and is used by the Food and Nutrition Board of the U.S. National Academies. The UL method requires evaluation of all sources of data and evidence. This assessment method was selected in advance of performance of the risk assessment. The AERs are not useful in identifying limits because they are not adequate to show causality. The risk assessment identified the conditions for safe use of ephedra supplements: dose limits, labeling, and post-market monitoring.

CRN urges FDA to adopt scientific conclusions based on the Cantox risk assessment on ephedra and is committed to work with FDA and other Federal authorities on appropriate implementation. CRN is submitting today the entire Cantox report for review by FDA.

Sincerely,
John N. Hathcock, Ph.D.
Vice President, Nutritional and Regulatory Science