[Federal Register Volume 66, Number 248 (Thursday, December 27, 2001)]
[Notices]
[Pages 66910-66912]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 01-31713]


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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.

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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availability for comment of draft guidance for industry entitled 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 This draft guidance is a 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 In this draft guidance, the agency recommends a pathway 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concerning this draft guidance by March 27, 2002 to ensure the 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ADDRESSES: Submit written comments on the draft guidance to the Dockets 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with the full title of the draft guidance and the docket number found 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    Submit written requests for single copies of the draft guidance to 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: 
afernand@cvm.fda.gov.
    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\
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                                                                     No. of       Annual Frequency    Total Annual        Hours per
                           Guidance                                Respondents      per Response        Responses         Response         Total Hours
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Assessments (including studies) of safety of antimicrobial             5                 1                 5            14,110            70,550
 drug residues that are microbiologically active in the human
 colon
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\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