[Federal Register Volume 65, Number 64 (Monday, April 3, 2000)]
[Notices]
[Pages 17510-17512]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-8283]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 00N-1200]


Dietary Supplements Containing Ephedrine Alkaloids; Availability

    ACTION: Notice of availability.
    SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of certain new adverse event reports (AER's) and related 
information, the vast majority of which were received after publication 
of the proposed rulemaking on dietary supplements containing ephedrine 
alkaloids. The agency is also announcing its intention to participate 
in a public forum to address this new information. This document is 
being issued to ensure that interested persons are aware of the new 
information the agency has available on these products and its plans to 
seek public input on this new information. Elsewhere in this issue of 
the Federal Register, FDA is withdrawing certain provisions of the 
proposed rule on dietary supplements containing ephedrine alkaloids and 
making available certain documents to update the administrative docket 
of that proposal.
    DATES: Submit written comments by May 18, 2000.
    ADDRESSES: Submit written comments on the information in this 
docket to the Dockets Management Branch, Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document.
    FOR FURTHER INFORMATION CONTACT: Marquita B. Steadman, Center for 
Food Safety and Applied Nutrition (CFSAN) (HFS-007), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20852, 301-827-6733. A 
contact person for the public forum will be announced in the near 
future.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of June 4, 1997 (62 FR 30678), FDA 
published a proposed rule on dietary supplements containing ephedrine 
alkaloids (hereinafter referred to as ``the ephedrine alkaloids 
proposal''). FDA proposed to establish a finding that a dietary 
supplement is adulterated if it contains 8 milligrams (mg) or more of 
ephedrine alkaloids per serving within a 6-hour period or a total daily 
intake of 24 mg or more of ephedrine alkaloids (``dosing level'' or 
``dietary ingredient level''), and to require the label of such 
supplement state that the product is not to be used for more than 7 
days (``duration of use limit''). In addition, FDA proposed to require 
certain warning statements, and to affect other aspects of labeling for 
such products. FDA proposed this action after receiving over 800 
adverse events associated with the use of dietary supplements that 
contained, or were suspected to contain, ephedrine alkaloids, and 
reviewing scientific literature and other data concerning ephedrine 
alkaloids. FDA received approximately 14,775 comments in response to 
the ephedrine alkaloids proposal.
    The House Committee on Science requested that the Government 
Accounting Office (GAO) examine the scientific bases for the ephedrine 
alkaloids proposal, and the agency's adherence to the regulatory 
analysis requirements for Federal rulemaking. On August 4, 1999, GAO 
publicly released its report entitled ``Dietary Supplements: 
Uncertainties in Analyses Underlying FDA's Proposed Rule on Ephedrine 
Alkaloids.'' A copy of this report is available in Docket No. 95N-0304.
    Generally, the GAO concluded that FDA was justified in determining 
that the number of AER's relating to dietary supplements containing 
ephedrine alkaloids warranted the agency's attention and consideration 
of steps to address safety issues. In addition, the GAO concluded that 
the available scientific information suggests that the use of products 
containing synthetic ephedrine alkaloids can result in adverse 
experiences for some individuals. However, GAO expressed concerns about 
the use of the adverse events in supporting the proposed dosing level 
and duration of use limit, and concluded that the agency needed 
additional evidence to support these restrictions.
    GAO also concluded that FDA's economic analysis contained the basic 
elements expected in a Federal agency's cost-benefit analysis and that 
the ephedrine alkaloids proposal complied with regulatory flexibility 
analysis requirements under the Regulatory Flexibility Act. GAO noted, 
however, that FDA's cost-benefit analysis was not always transparent 
regarding why certain key assumptions were made, the degree of 
uncertainty involved in those assumptions, or the effect that 
alternative assumptions would have had on the agency's estimates of the 
costs and benefits of the proposed action.
    GAO recommended that FDA ``provide stronger evidence on the 
relationship between the intake of dietary supplements containing 
ephedrine alkaloids and the occurrence of adverse reactions that 
support the proposed dosing level and duration of use limits.'' In 
addition, GAO recommended that FDA improve the transparency of its 
cost-benefit analysis in its final rulemaking.
    Before the GAO report was released, FDA had already begun 
accumulating and evaluating data on additional adverse events reported 
to the agency since the publication of the ephedrine alkaloids proposal 
as well as initiating a process to obtain outside scientific input and 
review. Since publication of the ephedrine alkaloids proposal and 
following release of the GAO report, FDA has continued to receive 
reports of adverse events, conducted its own independent evaluations 
and analyses, and continued to seek input from outside experts on these 
issues. FDA is now making available new information, the vast majority 
of which it has received since publication of the ephedrine alkaloids 
proposal.

II. New Information--Docket No. 00N-1200

    To gain a better perspective on the significance of the public 
health concern and public health problems associated with the current 
use of dietary supplements containing ephedrine alkaloids, CFSAN 
applied its available resources towards conducting

[[Page 17511]]

an analysis of 140 AER's with a report date (date the adverse event 
form was completed) period of June 1, 1997, through March 31, 1999, 
(``New Case Series''). CFSAN chose the June 1, 1997, date because it 
was close to the publication date of FDA's ephedrine alkaloids 
proposal. CFSAN chose the March 31, 1999, cut-off date so that it could 
have a closed set of data to analyze and prepare for public release. 
These adverse events, reported during the time period June 1, 1997, 
through March 31, 1999, had not previously received a comprehensive 
clinical analysis by the agency. All AER's received by FDA within that 
timeframe were included in the analysis. CFSAN's evaluation included an 
initial screening to determine whether the quality of the evidence 
available was sufficient to support a more comprehensive clinical 
evaluation of those adverse events that met the screening criteria. 
These criteria are identified in a document entitled ``Assessment of 
Public Health Risks Associated with the Use of Ephedrine Alkaloid-
Containing Dietary Supplements'' which is available in this docket. 
(See section IV of this document for a more detailed outline of this 
document.) CFSAN used only those adverse events judged to have 
sufficient information for further evaluation. Following the initial 
screening of these reports, eight were eliminated from further review. 
The remaining 132 cases were subjected to an in-depth clinical review. 
CFSAN has also obtained a clinical review of 139 of the 140 adverse 
events in the New Case Series from FDA's Center for Drug Evaluation and 
Research (CDER). (One of the adverse events in the New Case Series 
reviewed by CFSAN was not identified as being within the designated 
time period for the New Case Series until after CDER's review began.)
    As part of FDA's overall evaluation, it also contracted with 
outside scientific and clinical experts to obtain additional evaluation 
on dietary supplements containing ephedrine alkaloids, including the 
same 139 adverse events that CDER reviewed. FDA also conducted a market 
review covering August 1999 through March 2000 to determine whether 
there have been changes in the marketplace, including identification of 
new products containing ephedrine alkaloids.
    A listing of this new information is provided in section IV of this 
document.

III. Pre-case and Post-case Series

    FDA has received additional new AER's that have not been placed in 
any docket, and fall outside of the New case series timeframe (e.g., 
June 1, 1997, through March 31, 1999). Of these adverse events, 14 were 
reported before May 31, 1997, (``Pre-case series''). Moreover, 119 were 
reported beginning from April 1, 1999, and received by FDA by December 
31, 1999, with any additional followup information received by February 
15, 2000 (``Post case series''). Neither FDA nor its outside experts 
have conducted a comprehensive clinical analysis of the AER's in the 
Pre-case and Post-case series. FDA is announcing the availability of 
the Pre-case and Post-case series in this document.

IV. Public Docket

    FDA is establishing a new docket [Docket No. 00N-1200] and making 
available at the Dockets Management Branch (address above) for public 
inspection the following documents:
    1. One hundred and Fourty redacted AER's with a report date during 
the time period June 1, 1997, through March 31, 1999, (``New Case 
Series'') associated with dietary supplement products that were known 
or suspected to contain ephedrine alkaloids.
    2. A document entitled ``Assessment of Public Health Risks 
Associated with the Use of Ephedrine Alkaloid-containing Dietary 
Supplements,'' which includes the following sections:
      a. Section One: Overview/Background
      b. Section Two: CFSAN's Evaluation of New Case Series. This 
evaluation included an initial screening to determine whether the 
quality of evidence available was sufficient to support a more 
comprehensive clinical evaluation. CFSAN subjected only those adverse 
events judged to have sufficient information to further evaluation. 
Following the initial screening of these reports, 8 of the 140 were 
eliminated from further review. The clinical evaluation of the 
remaining reports resulted in the following classifications: (1) 
Adequate information to evaluate the relationship of product use to the 
adverse event and (2) insufficient data to further assess clinically or 
nonsupportive of a relationship between dietary supplements containing 
ephedrine alkaloids and the adverse event. Each of the reports with 
adequate information was reviewed and classified further into 
``attributable'' and ``supporting''. The criteria for ``attributable'' 
and ``supporting'' are explained in the document.
      c. Section Three: CFSAN's Review of the Published Literature on 
the Physiological, Pharmacological and Toxic Effects of Ephedrine 
Alkaloids.
      d. Section Four: Bibliography of Scientific References/citations 
for documents a through c above.
      e. Section Five: Appendices to Section Two above.
    3. FDA's Center for Drug Evaluation and Research's review of AER's 
associated with dietary supplements containing ephedrine alkaloids, 
including a clinical review of 139 of the adverse events evaluated in 
CFSAN's New Case Series.
    4. Reports from Outside Consultants concerning the following 
clinical/scientific reviews:
      a. Raymond Woosley, M.D., Ph.D., Review of 139 of the adverse 
events in the New Case Series and the likelihood of the events being 
associated with ephedrine alkaloids.
      b. Neal Benowitz, M.D., Review of 139 of the adverse events in 
the New Case Series and the likelihood of the events being associated 
with ephedrine alkaloids.
      c. Andrew L. Stoll, M.D., Review of specific 
neuropsychiatrically-related adverse events from the New Case Series 
and the likelihood of the events being associated with ephedrine 
alkaloids.
      d. George A. Ricaurte, M.D., Ph.D., Review of specific 
nerologically-related adverse events from the New Case Series and the 
likelihood of the events being associated with ephedrine alkaloids.
      e. Ka Kit Paul Hui, M.D., Opinion on the use of ephedra by 
practitioners trained in Traditional Chinese Medicine, including 
conditions, dosages, interactions, and duration of use.
      f. Mario Inchiosa, Ph.D., Scientific literature search and 
evaluation of the pharmacokinetics of naturally-occurring ephedrine 
alkaloids and synthetic ephedrine alkaloids.
      g. Alexander Walker, M.D., Dr. P.H., Statement concerning the 
likely reporting rate of adverse events involving dietary supplements.
    5. Fourteen redacted AER's with a report date before May 31, 1997, 
which have not been placed in any docket (``Pre-case series'') 
concerning dietary supplements containing ephedrine alkaloids. These 
AER's have not received an extensive clinical analysis by FDA.
    6. One hundred and nineteen redacted adverse events with report 
dates beginning April 1, 1999, and received by FDA by December 31, 
1999, with followup information received by February 15, 2000 (``Post-
case series'') concerning dietary supplements containing ephedrine 
alkaloids. These

[[Page 17512]]

AER's have not received an extensive clinical analysis by FDA.
    7. CFSAN Market Review--FDA review covering the period August 1999 
through March 2000 to determine whether there have been changes in the 
types of ephedrine alkaloid containing dietary supplement products 
available in the marketplace since the agency's review in 1995-1996.
    Several parties have informed the agency that, since the issuance 
of the ephedrine alkaloids proposal, there is new usage data, and new 
scientific information, including clinical trials sponsored by 
manufacturers, that supports the safety of dietary supplements 
containing ephedrine alkaloids. FDA has not been provided this 
information to date and encourages interested persons to submit this 
information and any other information the submitter believes is 
relevant to assessing the safety of dietary supplements containing 
ephedrine alkaloids. FDA encourages interested persons to submit this 
information to this docket by May 18, 2000, so that it will be 
available to the public and the agency for review.
    Interested persons may submit to the Dockets Management Branch 
(address above) written comments on the availability. Two copies of any 
comments are to be submitted, except that individuals may submit one 
copy. Comments are to be identified with the docket number found in 
brackets in the heading of this document. These documents and any 
received comments may be seen by interested persons at the Dockets 
Management Branch between 9 a.m. and 4 p.m., Monday through Friday.

V. Public Forum

    A public forum for discussion of the documents being made available 
in this document will be held at a date and location to be announced. A 
contact person for the public forum will also be announced.
    Written comments received in response to this document, and 
participation at the public forum, will assist the agency in 
determining appropriate next steps regarding dietary supplements 
containing ephedrine alkaloids.

    Dated: March 30, 2000.
William K. Hubbard,
Senior Associate Commissioner for Policy, Planning, and Legislation.
[FR Doc. 00-8283 Filed 3-31-00; 8:45 am]
BILLING CODE 4160-01-F