[Federal Register Volume 66, Number 155 (Friday, August 10, 2001)]
[Proposed Rules]
[Pages 42167-42170]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-20161]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 500

[Docket No. 01N-0284]
RIN 0910-AB71


Import Tolerances

AGENCY: Food and Drug Administration, HHS.

ACTION: Advance notice of proposed rulemaking.

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SUMMARY: The Food and Drug Administration (FDA) (we, the agency) is 
soliciting comment on issues related to the implementation of the 
import tolerances provision in section 4 of the Animal Drug 
Availability Act of 1996 (ADAA). The ADAA authorizes FDA to establish 
drug residue tolerances (import tolerances) for imported food products 
of animal origin for drugs that are used in other countries, but that 
are unapproved new animal drugs in the United States. Food products of 
animal origin that are in compliance with the import tolerance will not 
be considered adulterated under the Federal Food, Drug, and Cosmetic 
Act (the act) and may be imported into the United States. We plan to 
propose a regulation for establishing import tolerances. We plan to 
hold a public meeting on import tolerances during the comment period 
for this advance notice of proposed rulemaking (ANPRM) and intend to 
consider the comments made at the meeting and in response to this ANPRM 
in writing the proposed regulation. We also will work with the Food 
Safety Inspection Service of the United States Department of 
Agriculture and other Federal agencies in the development of the 
proposed regulation.

DATES: Submit written or electronic comments by December 10, 2001.

ADDRESSES: Submit written or electronic comments 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.

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FOR FURTHER INFORMATION CONTACT: Frances Pell, Center for Veterinary 
Medicine (HFV-235), Food and Drug Administration, 7500 Standish Pl., 
Rockville, MD 20855, 301-827-0188, e-mail: [email protected].

SUPPLEMENTARY INFORMATION:

I. Background on Import Tolerances

A. Import Tolerances--Legislative History and ADAA

    The President signed the ADAA into law on October 9, 1996. Section 
4 of the ADAA concerns import tolerances and amends section 512(a) of 
the act (21 U.S.C. 360b(a)) by adding the following new paragraph at 
the end:
    (6) For purposes of section [402(a)(2)(C)(ii)], a use or 
intended use of a new animal drug shall not be deemed unsafe under 
this section if the Secretary establishes a tolerance for such drug 
and any edible portion of any animal imported into the United States 
does not contain residues exceeding such tolerance. In establishing 
such tolerance, the Secretary shall rely on data sufficient to 
demonstrate that a proposed tolerance is safe based on similar food 
safety criteria used by the Secretary to establish tolerances for 
applications for new animal drugs filed under subsection (b)(1). The 
Secretary may consider and rely on data submitted by the drug 
manufacturer, including data submitted to appropriate regulatory 
authorities in any country where the new animal drug is lawfully 
used or data available from a relevant international organization, 
to the extent such data are not inconsistent with the criteria used 
by the Secretary to establish a tolerance for applications for new 
animal drugs filed under subsection (b)(1). For purposes of this 
paragraph, ``relevant international organization'' means the Codex 
Alimentarius Commission or other international organization deemed 
appropriate by the Secretary. The Secretary may, under procedures 
specified by regulation, revoke a tolerance established under this 
paragraph if information demonstrates that the use of the new animal 
drug under actual use conditions results in food being imported into 
the United States with residues exceeding the tolerance or if 
scientific evidence shows the tolerance to be unsafe.
The legislative history notes that ``the bill authorizes FDA to 
establish import tolerances for new animal drugs not approved in the 
United States'' and that a September 20, 1996, letter from the 
Director, United States Congress, Congressional Budget Office (CBO), to 
the Chairman, Committee on Commerce, includes a statement that CBO 
expects that the Secretary of Health and Human Services (the Secretary) 
would not set standards for these tolerances that are significantly 
different from current practice. H. Rept. 104-823 further clarifies the 
intention of section 4 of the ADAA by stating that the section 
authorizes FDA to establish import tolerances by ``using criteria 
similar to those that it would apply in reviewing the human food safety 
aspects of an animal drug for which approval is sought in the United 
States.'' In addition, the report states that FDA may rely on data 
generated by the drug manufacturer or on data from a relevant 
international organization such as the Codex Alimentarius Commission. 
The report further states that section 4 of the ADAA furthers 
international harmonization of regulatory requirements.
    It is currently unlawful to import animal-derived food that 
contains residues of a drug that is not approved in the United States, 
unless the Secretary has established an import tolerance for that drug 
and the residue does not exceed that tolerance. Any amount of residue 
from a drug not approved in the United States and for which no import 
tolerance exists, even a level of residue considered safe by the 
exporting country, would cause the food to be adulterated under section 
402(a)(1)(C)(ii) of the act (21 U.S.C. 342(a)(1)(C)(ii)), and denied 
entry into the United States under section 801(a)(3) of the act (21 
U.S.C. 381(a)(3)). It is also unlawful to import animal-derived food 
that contains residues of a drug approved in the United States, if the 
residues are present at levels above the established tolerance.
    Foreign drug sponsors may choose not to seek full approval in the 
United States for several reasons. It may be difficult for foreign drug 
sponsors to seek full approval in the United States, in part because 
the comprehensive nature of the approval requirements in the United 
States may require a foreign sponsor to perform studies in the United 
States that are difficult to arrange from outside the United States. In 
addition, for some drugs there is little incentive for a drug sponsor 
to obtain approval of the drug for use in the United States because the 
drug is used to treat animal disease that does not occur in the United 
States. In this case, the U. S. target animal safety and efficacy 
components of the NADA would not be relevant.
    Some exporting countries have many more animal drugs approved for 
use in some species than are currently approved for those species in 
the United States. Some of these drugs might qualify for approval in 
the United States, if a drug sponsor were willing to invest in the 
research studies needed to support approval. Some of these drugs may 
not be easily approved in the United States, because drug sponsors may 
not be able to meet one or more requirements of the NADA (21 U.S.C. 
360b(b)).

B. Human Food Safety Requirements for NADAs in the United States

    The human food safety evaluation of an NADA is predicated on the 
assumption that the drug product in question will be manufactured 
consistently from one batch to the next to the same standards of 
purity, strength, and identity as the product used to generate the 
human food safety data. The evaluation is also based on the particular 
conditions of use in the food-producing animal as proposed in the NADA. 
The human food safety data for an NADA typically include, but are not 
necessarily limited, to the following:
    1. Threshold Assessment--The sponsor generally provides data that 
allow the agency to conduct a threshold assessment to determine the 
potential of the new animal drug to cause cancer. The data typically 
include the results of a battery of genetic toxicity studies, the oral 
toxicity studies discussed below, and carcinogenicity information 
regarding structurally similar chemicals in published or proprietary 
literature.
    2. Oral Toxicity Data--The sponsor generally provides data that 
allow the agency to assess the oral toxicity of the new animal drug in 
the diet. The data are typically generated through a 90-day rodent and 
nonrodent mammalian oral toxicity study, a multigeneration rat 
reproduction study, and a rodent teratology study. The no-effect level 
dose from the most relevant study divided by a safety factor (typically 
100 or 1,000) is used to calculate an acceptable daily intake (ADI) for 
the animal drug in the human diet. Once the ADI is established, safe 
concentrations are calculated for total residues of the drug (the 
parent drug and all metabolites) in edible tissue.
    3. Total Residue and Metabolism Data--Total residue depletion and 
metabolism data are typically generated in studies conducted with a 
stable radiolabel of the parent drug. The total residue studies provide 
data on the concentration of the total residues of the drug in the 
edible tissues and changes in that concentration over time from the 
cessation of treatment. The metabolism studies are used to determine 
the nature and disposition of the residues in the edible tissues of the 
target animal.
    4. Target Tissue Determinations--Total residue and metabolism data 
are used to determine an appropriate target tissue which will serve as 
an index of the safety of all edible tissues in the target animal. The 
residues of a drug typically deplete at different rates for different 
edible tissues. The target tissue

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is usually the edible tissue that takes the longest to deplete, but 
other factors may also be considered when selecting the target tissue. 
The target tissue is selected such that when the concentration of drug 
residues is safe for consumption in the target tissue, all other edible 
tissue is also safe for consumption.
    5. Marker Analyte Determination--A marker analyte is determined to 
serve as a measurable index of the total residues of the drug in the 
target tissue. The marker analyte may be the parent drug, a metabolite 
of the parent, or a known combination of metabolites.
    6. Determinative and Confirmatory Regulatory Method--The sponsor 
generally provides a two part (determinative and confirmatory) 
analytical regulatory method to determine the concentration of the 
marker residue in the target tissue upon which to base the tolerance 
(see below). The regulatory method is also used in establishing the 
withdrawal time and in assuring the safety of food animals treated with 
the approved new animal drug.
    7. Tolerance--A tolerance is established based upon the 
relationship between the concentration of the marker analyte (measured 
by the determinative method) and the concentration of total residues of 
the drug (measured by radiolabel method) at the safe concentration. The 
concentration of the marker analyte in the target tissue, as measured 
by the regulatory method, which corresponds to the safe concentration 
for total residues of the drug in the target tissue, is defined as the 
tolerance.
    8. Withdrawal Study--The sponsor generally provides a withdrawal 
study (or depletion study) to determine the depletion time necessary 
from the cessation of treatment of the labeled target animal species at 
the maximum labeled dose and duration under normal conditions of use to 
the time when the marker residues in the target tissue are below the 
tolerance for that drug as measured by the regulatory method.
    The human food safety criteria listed above are provided for the 
information of the reader preparing comments in response to this ANPRM. 
Some of these criteria would have to be modified for establishing 
import tolerances. For example, whole animals usually would not be 
imported into the United States. Therefore, the target tissue for an 
import tolerance would be the type of tissue that is imported into the 
United States. A withdrawal study is an example of a study for the 
approval of an NADA for use of the drug in the United States that would 
not be necessary for establishing an import tolerance because data from 
the withdrawal study are not involved in the tolerance calculation. 
Other criteria, such as the requirement for the sponsor to submit a 
regulatory method, would remain the same.

II. Agency Request for Information

    FDA is soliciting comment on all aspects of import tolerances and 
specifically on the following issues:
    Issue 1: We set tolerances based upon the ADI and the relationship 
between the marker analyte and the total residue. To establish the 
tolerance, we consider conditions of use (including formulation, dose, 
and route of administration) and manufacturing features (including drug 
potency and purity). Regulatory agencies outside of the United States 
and international organizations may use different or additional factors 
to establish maximum residue levels (MRLs). The factors used by these 
regulatory agencies may include different edible tissue consumption 
factors or animal husbandry standards such as good agricultural 
practices. The effect of considering these factors may be a different 
tolerance value than the value established only on the basis of the 
human food safety data as presented in section I.B above.
    Question: There are different approaches that we could use to find 
a safe import tolerance. We could look at toxicity and residue data and 
build in a conservative safety factor. Alternatively, we could also 
review conditions of use such as good agricultural practices, route of 
administration, and dose, which may result in a different safety factor 
or factors. Additionally, we could consider manufacturing information 
such as that required for a domestic application, which also could 
result in a different safety factor or factors. Which approach is 
preferable?
    Issue 2: The tolerance established by FDA for a new animal drug 
approved under section 512(b)(1) of the act is based on data submitted 
by the sponsor. These data are owned by the drug sponsor 
(pharmaceutical company, producer organization, etc.) that paid for the 
study and is accountable for the quality of the research. Each 
subsequent sponsor seeking approval of the drug under section 512(b)(1) 
of the act must submit similar human food safety data as required to 
support the tolerance for their product. Each new animal drug tolerance 
is established for each drug product, rather than for the drug 
substance/active ingredient. However, the ADAA allows for data for an 
import tolerance to include ``data submitted by the drug manufacturer 
to appropriate regulatory authorities in any country where the new 
animal drug is lawfully used or data available from a relevant 
international organization* * * .'' Any country wanting its producers 
to become eligible to export to the United States, could be a sponsor 
of an import tolerance.
    Question: Only the drug marker residue for the drug substance, not 
the product formulation or the sponsor of the import tolerance, can be 
determined by the type of analytical method that is typically used to 
assay imports. Are there analytical techniques or other approaches that 
would allow us to determine whether a residue is due to use of the drug 
product for which the tolerance is approved?
    Issue 3: We are considering how we should inform the public of the 
import tolerance process while also ensuring that we do not disclose 
trade secrets and confidential commercial information.
    Questions:
    (a) Should we disclose to the public that we are considering an 
import tolerance for a new animal drug?
    (b) If so, when (e.g, upon request, upon filing)?
    (c) How should we do so (e.g., Federal Register, Internet)?
    (d) How much detail should we provide, keeping in mind that we 
cannot disclose trade secrets or confidential commercial information?
    Issue 4: We are considering amending the regulations at 21 CFR 
25.33 to allow a categorical exclusion for import tolerances under the 
National Environmental Policy Act, if there is information that shows 
that establishing import tolerances does not have a significant effect 
on the environment. We are seeking information on whether import 
tolerances will have a significant effect on the environment.
    Issue 5: Please comment on any other aspects of import tolerances 
you wish to raise.

III. Comments

    Interested persons may submit written or electronic comments 
regarding the advance notice of proposed rulemaking by December 10, 
2001. Written or electronic comments should be submitted to the Dockets 
Management Branch (address above). 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. Received comments may be seen in the office above 
between 9 a.m. and 4 p.m., Monday through Friday.
    Comments may also be submitted electronically on the Internet at: 
http://www.fda.gov/dockets/ecomments. Once

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on this Internet site, select 01N-0284 Import Tolerances and follow the 
directions.
    We intend to hold a meeting of the Veterinary Medicine Advisory 
Committee (VMAC) in September 2001. The committee will be asked to 
discuss answers to questions similar to those posed in the ANPRM. The 
notice of the date, time, and place for the meeting of the VMAC appears 
elsewhere in this issue of the Federal Register.
    This ANPRM is issued under section 4(e) of the ADAA, sections 201, 
402, 512, 701, and 801 of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 321, 342, 360b, 371, and 381), and under the authority of the 
Commissioner of Food and Drugs.

    Dated: July 16, 2001.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 01-20161 Filed 8-8-01; 11:44 am]
BILLING CODE 4160-01-S