[Federal Register: April 3, 2000 (Volume 65, Number 64)]
[Notices]
[Page 17510-17512]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr03ap00-56]
 
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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

Extension of Comment Period May 22, 2000 Federal Register

"Dear Colleague" Letter About August 8, 2000 Public Meeting Concerning the Safety of Dietary Supplements Containing Ephedrine Alkaloids June 8, 2000