[Federal Register Volume 66, Number 248 (Thursday, December 27, 2001)]
[Notices]
[Pages 66910-66912]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-31713]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 93D-0398]
Assessment of the Effects of Antimicrobial Drug Residues From
Food of Animal Origin on the Human Intestinal Flora; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability for comment of draft guidance for industry entitled
``Assessment of the Effects of Antimicrobial Drug Residues from Food of
Animal Origin on the Human Intestinal Flora.'' This draft guidance is a
revision of the guidance document no. 52 entitled ``Microbiological
Testing of Antimicrobial Drug Residues in Food,'' which was implemented
in 1996. In this draft guidance, the agency recommends a pathway
approach for assessing the microbiological safety of antimicrobial drug
residues in food, rather than the approach described in the 1996
version of the guidance. The agency's decision to revise this guidance
is based on new information available to the agency.
DATES: You may submit written or electronic comments at any time.
However, the agency would like to use these comments during the next
meeting of the International Cooperation on Harmonisation of Technical
Requirements for Registration of Veterinary Medicinal Products (VICH)
Microbial Safety Task Force meeting. You should submit comments
concerning this draft guidance by March 27, 2002 to ensure the
incorporation of your comments at that meeting.
Submit written or electronic comments on the collection of
information by February 25, 2002.
ADDRESSES: Submit written comments on the draft guidance to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to
http://www.fda.gov/dockets/ecomments. All comments should be identified
with the full title of the draft guidance and the docket number found
in brackets in the heading of this document.
Submit written requests for single copies of the draft guidance to
the Communications Staff (HFV-12), Center for Veterinary Medicine, Food
and Drug Administration, 7500 Standish Place, Rockville, MD 20855. Send
one self-
[[Page 66911]]
addressed adhesive label to assist the office in processing your
requests. See the SUPPLEMENTARY INFORMATION section for electronic
access to the guidance document.
FOR FURTHER INFORMATION CONTACT:
For information regarding the guidance document: Haydee Fernandez,
Center for Veterinary Medicine (HFV-150), Food and Drug Administration,
7500 Standish Pl., Rockville, MD 20850, 301-827-6981, e-mail:
[email protected].
For information regarding information collections and the Paperwork
Reduction Act: Denver Presley, Office of Information Resources
Management (HFA-250), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301-827-1462.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of January 30, 1996 (61 FR 3043), FDA
published a notice of availability for a guidance document entitled
``Microbiological Testing of Antimicrobial Drug Residues in Food''
(guidance no. 52). This guidance document stated that the agency would
consider antimicrobial activity as a valid endpoint for establishing
tolerances for antimicrobial drugs. The guidance also stated that
antimicrobial residues present in food from food-producing animals
should not cause any adverse effect on the ecology of the human
intestinal microflora of consumers. The guidance identified
antimicrobial drugs that would be exempt from additional
microbiological testing and those that would warrant testing. The
reasons for exempting certain antimicrobial drugs from additional
microbiological testing included ``very low'' residues present in the
food, residues with limited antimicrobial activity, and drugs with no
adverse effects on the intestinal microflora at therapeutic doses.
Guidance no. 52 stated that ``very low'' levels of antimicrobials
present in food would not perturb the intestinal microflora or select
for resistant microorganisms and, therefore, would be ``safe'' under
Section 512 of the Federal Food, Drug, and Cosmetic Act. Based on the
best information available at that time, FDA believed that a maximum
Acceptable Daily Intake (ADI) of 1.5 milligram (mg)/person/day of
microbiologically active residues present in the food qualified as
``very low'' residues and should not produce adverse effects on the
intestinal microflora. After CVM established the maximum ADI of 1.5 mg/
person/day in the 1996 version of guidance no. 52, CVM staff publicly
(e.g., at a workshop sponsored by FDA on September 20 and 21, 1999, in
Rockville, MD) stated that this threshold would need to be re-evaluated
when additional information was obtained on the adequacy of this number
for different classes of antimicrobial drugs.
The guidance recommended that additional microbiological testing be
performed for those antimicrobial drugs for which sponsors were seeking
an ADI higher than 1.5 mg/person/day. The guidance document identified
the following areas for which antimicrobial residues present a
potential public health concern. These endpoints are: (1) Changes in
the metabolic activity of the intestinal microflora, (2) changes in
antimicrobial resistance patterns of the intestinal microflora, (3)
changes in the colonization resistance properties (barrier effect) of
the microflora, and (4) changes in the number of microorganisms and
composition of the intestinal microflora. The guidance recommended that
sponsors characterize the product, identify its microbiological
activity, and monitor the appropriate microbiological endpoints in
order to establish the antimicrobial no-observed effect level (NOEL).
Because no validated model systems were available at that time, FDA
announced its intention to validate model systems to evaluate the
effect of low levels of antimicrobial drugs on endpoints of public
health concern. The guidance also stated that in vitro microbiological
inhibitory concentration data should not be submitted to establish the
microbiological NOEL, because these data do not predict the level of
drug residues that would elicit the potential public health concern.
Sponsors were encouraged to consult with CVM to determine appropriate
protocols before conducting studies.
In 1995, CVM funded two extramural research contracts to study the
dose-response effects of antimicrobial drugs on human intestinal
microflora endpoints that could be of public health concern. In a
workshop sponsored by FDA on September 20 and 21, 1999, in Rockville,
MD, information from the two research contracts was presented. Data on
the effect of low doses of different classes of antimicrobials on
several microbiological endpoints of the human intestinal microflora
were discussed. After reviewing and discussing the data, FDA concluded
that the threshold ADI discussed in guidance no. 52 is not appropriate
for all classes of antimicrobials. Different classes of antimicrobials
affect, to different degrees, microbiological endpoints that could be
of public health concern. Therefore, FDA has decided to modify guidance
no. 52 to recommend that sponsors use a pathway approach (described in
the draft guidance) for addressing human food safety of antimicrobial
drug residues, rather than the approach described in the 1996 version
of the guidance. The scientific rationale for this decision is provided
in the appendix of the draft guidance document.
Guidance no. 52 may be further revised at a later date according to
the recommendations from VICH concerning proper tests and model systems
and standard protocols for addressing endpoints of public health
concern. VICH also needs to address how to calculate ADIs using NOELs
obtained from microbiological testing models. However, the agency
believes that it is in the best interest of the regulated industry and
public health to revise guidance no. 52 now, instead of waiting for the
VICH recommendations to be completed.
This level 1 guidance is being issued consistent with FDA's good
guidance practices regulation (21 CFR 10.115). This draft guidance,
when finalized, will represent the agency's current thinking with
regard to the approach that should be used to assess the
microbiological safety of antimicrobial drug residues in food of animal
origin. It does not create or confer any rights for or on any person
and does not operate to bind FDA or the public. An alternate method may
be used as long as it satisfies the requirements of applicable statutes
and regulations.
II. Paperwork Reduction Act of 1995
Under the Paperwork Reduction act of 1995 (the PRA) (44 U.S.C.
3501-3520), Federal agencies must obtain approval from the Office of
Management and Budget (OMB) for each collection of information they
conduct or sponsor. ``Collection of information'' is defined in 44
U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes agency requests or
requirements that members of the public submit reports, keep records,
or provide information to a third party. Section 3506(c)(2)(A) of the
PRA (44 U.S.C. 3506(c)(2)(A)) requires Federal agencies to provide a
60-day notice in the Federal Register concerning each proposed
collection of information, including each proposed collection of an
existing collection of information, before submitting the collection to
OMB for approval. To comply with this requirement, FDA is publishing a
notice of the proposed collection of information set forth in this
document.
[[Page 66912]]
With respect to the following collection of information, FDA
invites comments on: (1) Whether the proposed collection of information
is necessary for the proper performance of FDA's functions, including
whether the information will have practical utility; (2) the accuracy
of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Assessment of the Effects of Antimicrobial Drug Residues
from Food of Animal Origin on the Human Intestinal Flora
Description: Sponsors of new animal drugs must meet certain
statutory requirements for new animal drug approval under section 512
of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360b). Among
other things, the sponsor must demonstrate that the use of the drug is
safe. Thus, when CVM reviews new animal drug applications for drugs
that will be used in food-producing animals, it must determine whether
residues of the drug that may remain in human food derived from those
animals would be harmful to humans. One possible harmful effect of
residues of antimicrobial drugs that CVM considers in this
determination is the possible effect of residues on human intestinal
flora.
This draft guidance document describes the recommended pathway
approach for assessing such effects. An assessment of the safety of
antimicrobial drug residues in food is a major issue that should be
addressed by the sponsor of a new animal drug. For residues determined
to have no antimicrobial activity against representatives of the human
intestinal flora, an ADI should be calculated based on traditional
toxicology studies. The burden hours required are reported and approved
under OMB Control No. 0910-0032. However, the draft guidance recommends
that additional information be provided for certain drugs. This
additional information should be provided if an assessment of
microbiological safety determines that a new animal drug produces
residues in foods that are microbiologically active in the human colon.
The likely respondents to this collection of information are sponsors
of antimicrobial new animal drugs that will be used in food-producing
animals.
FDA estimates the burden of this collection of information as
follows:
Table 1.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
No. of Annual Frequency Total Annual Hours per
Guidance Respondents per Response Responses Response Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
Assessments (including studies) of safety of antimicrobial 5 1 5 14,110 70,550
drug residues that are microbiologically active in the human
colon
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
The estimates in table 1 of this document resulted from discussions
with sponsors of new animal drugs. The estimated burden includes
studies, analysis of data, and writing the assessment. The number of
respondents provided is based on current experience, however, the
number may change in the future.
III. Comments
This draft guidance document is being distributed for comment
purposes only and is not intended for implementation at this time.
Interested persons may submit to the Dockets Management Branch (address
above) written or electronic comments regarding this draft guidance
document. Submit written or electronic comments by March 27, 2002 to
ensure adequate consideration by the VICH Microbial Safety Task Force
and in the development of the final guidance. 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. A copy of the draft guidance
and received comments are available for public examination in the
Dockets Management Branch between 9 a.m. and 4 p.m., Monday through
Friday.
Submit written comments concerning the information collection
requirements to the Dockets Management Branch by March 27, 2002. A copy
of the document and received comments are available for public
examination in the Dockets Management Branch between 9 a.m. and 4 p.m.,
Monday through Friday.
IV. Electronic Access
Electronic comments may be submitted electronically on the Internet
at http://www.fda.gov/dockets/ecomments. Once on this Internet site,
select [Insert Docket Number for this publication] ``Assessment of the
Effects of Antimicrobial Drug Residues from Food of Animal Origin on
the Human Intestinal Flora'' and follow the directions. Copies of the
draft guidance entitled ``Assessment of the Effects of Antimicrobial
Drug Residues from Food of Animal Origin on the Human Intestinal
Flora'' may be obtained on the Internet from the CVM home page at
http://www.fda.gov/cvm.
Dated: December 18, 2001.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 01-31713 Filed 12-26-01; 8:45 am]
BILLING CODE 4160-01-S