[Federal Register Volume 67, Number 23 (Monday, February 4, 2002)]
[Rules and Regulations]
[Pages 5046-5061]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-2549]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 211, 226, 510, and 514

[Docket No. 88N-0038]
RIN 0910-AA02


Records and Reports Concerning Experience With Approved New 
Animal Drugs

AGENCY: Food and Drug Administration, HHS.

ACTION: Interim final rule; opportunity for public comment.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
requirements for records and reports of adverse experiences and other 
information for approved new animal drugs. This interim final rule more 
clearly defines the kinds of information to be maintained and submitted 
by new animal drug applicants for a new animal drug application (NADA) 
or an abbreviated new animal drug application (ANADA). In addition, the 
interim final rule revises the timing and content of certain reports to 
enhance their usefulness. The regulation will provide for protection of 
public and animal health and reduce unnecessary recordkeeping and 
reporting requirements.

DATES: This interim rule is effective August 5, 2002. Submit written or 
electronic comments on new information on the interim final rule and 
the information collection requirements by April 5, 2002. Please note 
the agency will not consider any comments that have been previously 
considered during this rulemaking.

ADDRESSES: Submit written comments on the information collection 
requirements to the Dockets Management Branch (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. 
Submit electronic comments on the Internet at http://www.fda.gov/dockets/ecomments. All comments should be identified with the docket 
number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: William C. Keller, Center for 
Veterinary Medicine (HFV-210), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-827-6641, or 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Introduction

    In the Federal Register of December 17, 1991 (56 FR 65581), FDA 
(we) published a proposed rule (the proposed rule for records and 
reports) to revise Sec. 510.300 (21 CFR 510.300) and to redesignate it 
as Sec. 514.80 (21 CFR 514.80). This regulation implements section 
512(l) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
360b(l)) which provides that, following approval of an NADA or ANADA, 
applicants must establish and maintain records and make reports to the 
agency as prescribed by regulation or order. We proposed the revision 
in order to more clearly define the kinds of information to be 
maintained and submitted by the applicant and to revise the timing and 
content of certain reports to enhance the usefulness of the 
information.
    After considering comments submitted in response to the proposed 
rule for records and reports, FDA is adopting the rule in modified 
form. The scope and coverage of this interim final rule differs in some 
respects from the proposed rule for records and reports. The proposed 
rule for records and reports covered NADAs, ANADAs, and medicated feed 
applications (MFAs). In contrast, the interim final rule covers only 
NADAs and ANADAs. The Animal Drug Availability Act of 1996 (ADAA) (21 
U.S.C. 360b(a) and 360b(m)) amended the statutory provisions in the act 
regarding medicated feeds and eliminated MFAs. Therefore, the interim 
final rule does not address MFAs. However, the interim final rule 
retains reporting requirements for serious adverse drug experiences 
with feeds incorporating approved Type A medicated articles.
    While the proposed rule for records and reports proposed to remove 
21 CFR 510.310, which addressed records and reports for new animal 
drugs approved before June 20, 1963, we issued a final rule that 
revoked this provision in response to the Administration's 
``Reinventing Government Initiative'' (61 FR 37680, July 19, 1996).
    The proposed rule for records and reports followed a style and 
format similar to the human drug records and reports regulations in 
part 314 (21 CFR part 314). The interim final rule maintains a similar 
style and format, but removes many of the proposed records and reports 
requirements that are not necessary to monitor animal drugs.
    In response to concerns over duplicate reporting, FDA has removed 
proposed Sec. 514.82, which concerned records and reports from 
manufacturers, packers, labelers, and distributors other than the 
applicant. However, the agency has retained certain record and report 
requirements for nonapplicants (defined in new Sec. 514.3(f)) in 
Sec. 514.80(b) of this interim final rule.
    For purposes of clarity, the agency has made some changes to the 
text and organization of the interim final rule. The following list 
provides examples of changes not intended to affect the substantive 
requirements of the rule:
     All definitions in the proposed rule for records and 
reports have been consolidated in new Sec. 514.3 Definitions. 
Specifically, definitions for the terms ``applicant'' and 
``nonapplicant'' that appeared in text of the proposed rule for records 
and reports have now been moved to Sec. 514.3.
     Proposed Sec. 514.80(a) discussed the requirements for 
``establish[ing] and maintain[ing] records and mak[ing] reports'' in 
one paragraph. For easier reading, FDA has broken the paragraph down in 
this interim final rule to discuss the recordkeeping and reporting 
requirements separately.
     New Sec. 514.80(a)(2) discusses the reporting requirements 
in slightly greater detail than had been done in the proposed rule. 
This is intended to provide a road map of the requirements contained in 
other parts of the interim rule.
     Final Sec. 514.80(a)(5) was added to clarify that the 
records and reports referred to in this section are in addition to 
those required by the current good manufacturing practice regulations.
     The interim final rule combines the proposed periodic 
adverse drug experience reports with the proposed annual reports 
(designated as Sec. 514.80(d)(3) and (d)(4), respectively, in the 
proposed rule), because both reports require the same information. The 
combined report, which is now found at Sec. 514.80(b)(4), is entitled 
``Periodic drug experience report'' in the interim final rule.
     Reporting requirements for reports of adverse drug 
experiences in the

[[Page 5047]]

published literature were found in the proposed rule in the ``General 
requirements'' section (proposed Sec. 514.80(e)). Similarly, reporting 
requirements for adverse drug experiences that occur during 
postapproval studies were also found in this section in the proposed 
rule. Because both of these requirements are part of the ``Periodic 
drug experience report,'' these sections have been moved in the interim 
final rule to Sec. 514.80(b)(4) Periodic drug experience report. 
Specifically, the requirements for reports of adverse drug experiences 
in the published literature are now found in final 
Sec. 514.80(b)(4)(iv)(B), and requirements for adverse drug experiences 
that occur during postapproval studies are now found in final 
Sec. 514.80(b)(4)(iv)(C).

II. Response to Comments

    The agency received 12 comments on the proposed rule for records 
and reports, 8 NADA applicants, 3 industry associations, and 1 
association of regulatory professionals. A discussion of the comments 
and our response follows. Because sections of the proposed rule have 
been rearranged in the interim final rule, we are providing the 
following conversion tables to aid readers in comparing the proposed 
and interim final rules:

                           Conversion Table 1.
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            Proposed Rule Section             Interim Final Rule Section
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514.80(a) Applicability                       514.80(a)
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514.80(b) Definitions                         514.3
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514.80(c) Records to be maintained            514.80(e)
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514.80(d) Reporting requirements              514.80(b)
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514.80(d)(5)(iii) Statements of NADA          Not included in interim
 approval status                               final rule
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514.80(e) General requirements                514.80(c)
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514.80(f) Reporting forms                     514.80(d) and 514.80(g)
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514.80(g) Access to records and reports       514.80(f)
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514.80(h) Withdrawal of approval              514.80(h)
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514.81 Records and reports concerning         Not included in interim
 experience with animal feeds bearing or       final rule
 containing new animal drugs for which an
 approved application is in effect
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514.82 Records and reports concerning         514.80(b)(3)
 experience with new animal drugs from
 manufacturers, packers, labelers, and
 distributors other than the applicant
------------------------------------------------------------------------

A. General Comments

    (Comment 1) A number of comments questioned the need to change the 
existing regulation. These comments characterized the proposed changes 
as an unnecessary effort to make the animal drug regulations mimic the 
parallel regulations for human drugs. The comments emphasized the 
differences between human and veterinary medicine in treatment goals, 
dosing protocols, and evaluation of treatment responses. In light of 
these differences, the comments suggested that the record and reporting 
regulation for animal drugs should differ from the regulation for human 
drugs.
    We agree that the regulations for human and animal drugs should 
differ in some areas. We changed the interim final rule in response to 
specific comments. Thus, the changes make the human and animal drug 
regulations similar but not identical.
    (Comment 2) Some comments criticized our estimates of the annual 
reporting and recordkeeping burden. We estimated the proposed rule 
would require an additional 400 responses above the number required 
under the previous regulation from 200 businesses. The estimated 
increased total annual workload from the proposed rule was 200 hours, 
or approximately 1 hour per business. Representatives of the animal 
drug industry suggested that the added reporting burden would be 930 
hours per respondent, with a total burden of 186,000 hours per year. 
This comment suggested that 500 hours per year were attributable to the 
proposed NADA-field alert report (proposed Sec. 514.80(d)(1)), 90 hours 
per year to the proposed 15-day alert report followups (proposed 
Sec. 514.80(d)(2)(ii)), 60 hours per year to the proposed periodic 
adverse drug experience reports (proposed Sec. 514.80(d)(3)), and 280 
hours per year to the proposed annual report (proposed 
Sec. 514.80(d)(4)). The comments stated that the added burden was 
unjustified in the absence of any significant threat to the public 
health.
    Our estimates of the annual reporting and recordkeeping burden in 
the proposed rule addressed only the increased burden resulting from 
the new provisions of the proposed regulation. The estimate did not 
include the workload resulting from previously existing provisions of 
the regulation. We have amended the estimated reporting and 
recordkeeping burden charts to reflect the total burden of the rule. 
Furthermore, our estimates are for the number of hours required to 
complete each response, not the number of hours per year per NADA 
holder as suggested in the comment. Thus, FDA's estimates are not 
directly comparable to those in the comment.
    Additionally, the agency has made revisions in this interim final 
rule to provide for reduced reporting requirements under appropriate 
circumstances, thereby substantially reducing the reporting burden 
compared to the proposed rule. We have changed the reporting 
requirement for the 3-day NADA/ANADA field alert reports in the interim 
final rule (Sec. 514.80(b)(1)) so that applicants or nonapplicants must 
include only information pertaining to ``product and manufacturing 
defects that may result in serious adverse drug events'' instead of 
``any manufacturing defect'' as was required in the proposed rule for 
records and reports (proposed Sec. 514.80(d)(1)). This change will 
reduce the recordkeeping burden for this provision to a total of 60 
hours.
    Further, the periodic adverse drug experience report and annual 
report proposed in Sec. 514.80(d)(3) and (d)(4) were combined into a 
single periodic drug experience report under Sec. 514.80(b)(4). 
Finally, we agreed with comments that the requirement in 
Sec. 514.80(d)(3) of the proposed rule for quarterly submissions of 
periodic drug experience reports for 3 years was excessive. Thus, the 
agency reduced this reporting requirement in Sec. 514.80(b)(4) of the 
interim final rule to every 6 months for the first 2 years. The interim 
final rule requires 5 periodic drug experience reports within 3 years 
of approval; the proposed rule required 12 periodic drug experience 
reports within 3 years of approval.
    We added provisions in interim final Sec. 514.80(b)(4) that allow 
applicants to petition us to change the date of submission of yearly 
periodic drug experience reports or the frequency of reporting to 
intervals greater than annually. This provision will substantially 
reduce the number of periodic drug experience reports.

[[Page 5048]]

B. Definition of an Adverse Drug Experience (New Sec. 514.3(a))

    (Comment 3) Several comments characterized the phrase ``whether or 
not considered drug-related'' found in the proposed definition of 
``adverse drug experience'' as being too broad in scope.
    We agree that the definition is broad. However, we believe that 
such a broad definition is necessary in light of the agency's goal to 
encourage reporting that captures all possible adverse drug 
experiences. For example, it is often difficult to determine drug-
relatedness in an individual case, but FDA, by seeing many reports, may 
see drug-relatedness that is not clear in individual instances. To 
prevent under-reporting and the possibility that rare or unexpected 
adverse drug reactions may be missed, the agency has decided to adopt 
the definition as proposed. However, in response to concerns over the 
implications of a broad definition, the agency has added a disclaimer 
in new Sec. 514.80(i) which states that submission of a report or 
information does not necessarily constitute a conclusion or admission 
that a drug caused or contributed to an adverse effect.
    (Comment 4) One comment suggested that reporting of adverse drug 
experiences be limited to ``significant or meaningful events.''
    We believe that limiting reporting as suggested could hinder 
postapproval surveillance because the significance of an event may not 
be apparent at the time of its occurrence. We desire to maintain and 
increase the availability and diversity of new animal drugs without 
compromising their safety and effectiveness. Postapproval reporting 
provides a source of vital information about the continued safety and 
effectiveness of a drug product over an extended period of time under 
field conditions. Therefore, we are maintaining the scope of the record 
and reporting requirements in this interim final rule.
    (Comment 5) One comment questioned the rationale for defining 
``adverse drug experience'' to include adverse events occurring in 
humans from exposure during manufacture, testing, handling, or use of a 
new animal drug. Several comments suggested that monitoring human 
health problems associated with exposure to new animal drugs is a 
responsibility of the Occupational Safety and Health Administration 
(OSHA) rather than FDA.
    Under the act, we are required to consider the human health factor 
when approving new animal drugs. For example, FDA requires that 
appropriate warnings regarding potential adverse effects to human 
health be included in the labeling of new animal drugs. FDA's role in 
worker safety is complementary to OSHA's role. Furthermore, not all 
human exposure to new animal drugs would be through occupational 
exposure. We believe continued reporting of human adverse drug 
experiences as related to animal drugs is appropriate and important. 
This reporting provides the agency with the information it needs to 
fulfill its mandate to consider human health effects. Thus, the agency 
is retaining this element of the definition in the interim final rule.
    (Comment 6) Comments asserted that the language used in proposed 
Sec. 514.80(b)(1)(ii), (b)(1)(iii), and (b)(1)(iv) is inappropriate for 
new animal drugs. In particular, the comments questioned defining 
``adverse drug experience'' in these sections to include an ``adverse 
event occurring from animal drug overdose,'' an ``adverse drug event 
occurring from animal drug abuse,'' and an ``adverse event occurring 
from animal drug withdrawal.''
    We agree that the phrases are not appropriate for animal drugs. 
These sections have been removed from the definition of ``adverse drug 
experience'' in new Sec. 514.3(a) to more accurately reflect the 
practices of veterinary medicine and animal agriculture.
    (Comment 7) Some comments questioned the phrase ``failure of an 
animal drug product to produce its expected pharmacological action'' in 
the definition of ``adverse drug experience'' in proposed 
Sec. 514.80(b)(1)(v). Some of these comments suggested that the phrase 
be changed to say ``unusual failure of an animal drug product * * * '' 
and noted that when animals are treated as a group rather than 
individually, the failure of some animals to respond is considered 
normal.
    We agree that when groups of animals are treated, the failure of 
some individuals to respond to therapy can be considered normal. 
However, a perceived lack of effectiveness based on an unusual failure 
to respond to therapy is a valid reason to submit an adverse drug 
experience report. Failure of a drug to produce its expected 
pharmacological action (``lack of effectiveness'') may result in the 
underlying disease process progressing to a serious health problem. 
This health problem, therefore, is indirectly caused by the drug. The 
failure should be submitted in an adverse drug experience report. 
However, if the failure of some individuals to respond to therapy was 
expected (i.e., is listed in the labeling), this failure should be 
submitted in the periodic experience report. Thus, FDA has retained the 
phrase ``failure * * * to produce its expected pharmacological * * * 
effect'' in new Sec. 514.3(a)(2).
    The comments also asserted that clinical response rather than 
pharmacological action would more accurately describe the results being 
monitored.
    We agree that clinical effect is another appropriate monitor in 
addition to lack of pharmacological action. Based on these comments, 
the language in new Sec. 514.3(a)(2) has been revised to read ``Failure 
of a new animal drug to produce its expected pharmacological or 
clinical effect (lack of effectiveness).''

C. Definition of Increased Frequency (New Sec. 514.3(d))

    (Comment 8) Some comments stated that monitoring and reporting an 
increased frequency in the rate of reported occurrences of any 
particular adverse drug experience is impractical in animal 
agriculture. One comment suggested that reporting of ``increased 
frequency'' should be limited to certain types of new animal drug 
products.
    We believe that it is practical for applicants to monitor and 
report apparent increases in the number of reports concerning a 
specific type of adverse drug experience, after adjusting for any 
increase in drug use. Drug surveillance is important not just for 
identifying serious adverse drug reactions, but also for monitoring and 
accounting for any changes in the incidence of these same serious 
reactions. However, in response to concerns raised by the comments, we 
revised the definition of ``increased frequency'' in proposed 
Sec. 514.80(b)(2) in new Sec. 514.3(d) to limit required reporting to 
serious adverse drug events, expected or unexpected, after appropriate 
adjustment for drug exposure.

D. Definition of New Animal Drug Application (New Sec. 514.3(b) and 
(e))

    (Comment 9) One comment suggested that the definition of the term 
``NADA'' be removed from the section concerning records and reports 
``because it causes confusion by inclusion of abbreviated new animal 
drug applications (ANADAs) in its scope and this is the only subsection 
in Sec. 514 where they are mentioned.'' The comment suggested that the 
regulations be revised to mention both NADAs and ANADAs when 
appropriate.

[[Page 5049]]

    FDA agrees. We revised this interim final rule to mention both 
NADAs and ANADAs when appropriate. In addition, we moved the 
definitions of the terms ``NADA'' and ``ANADA'' to new Sec. 514.3.

E. Definition of Serious (New Sec. 514.3(h))

    (Comment 10) Proposed Sec. 514.80(b)(4) defined the term 
``serious,'' as it relates to adverse drug experiences, to include ``an 
adverse drug experience that is fatal, life-threatening, permanently 
disabling, requires hospitalization, or involves systemic drug or other 
intervention.'' Several comments asserted that the phrase ``or involves 
systemic drug or other intervention'' as it appeared in this proposed 
section is too broad and the phrase ``requires hospitalization'' does 
not accurately reflect drug use in animal agriculture.
    We agree with these comments. We have addressed these concerns by 
revising the definition of ``serious adverse drug experience,'' in new 
Sec. 514.3(h). The definition is now more specific and reads ``an 
adverse event that is fatal or life-threatening, requires professional 
intervention, or causes an abortion, stillbirth, infertility, 
congenital anomaly, prolonged or permanent disability, or 
disfigurement.'' By including ``requires professional intervention'' 
(e.g., under a veterinarian's care) as a criterion, we reasonably limit 
the number of reports that have to be submitted under this portion of 
the regulation. The reference to hospitalization has been deleted in 
this interim final rule.

F. Definition of Unexpected (New Sec. 514.3(i))

    (Comment 11) Comments stated that the agency did not provide an 
explanation in the preamble to the proposed rule as to why the agency 
proposed to change the definition of ``unexpected'' (in the context of 
adverse drug experiences). Comments also stated that the existing 
definition of ``unexpected'' should be retained or the proposed new 
definition should be simplified.
    FDA disagrees that the definition should be retained or simplified. 
In the preamble to the proposed rule, we did not explain why we 
proposed to change the definition of ``unexpected.'' The explanation is 
that the NADA or ANADA file is not publicly available, but the labeling 
is. Thus, ``unexpected'' adverse drug experiences should be provided in 
the labeling, so that anyone (not just someone with access to the NADA 
or ANADA file) can determine whether an event is unexpected.
    Thus, we are keeping the definition as proposed. That definition, 
which is now found in new Sec. 514.3(i), specifies that labeling, 
rather than the NADA or ANADA file, is the standard for comparison when 
deciding whether a reported event is an unexpected adverse drug 
experience.

G. Definitions of Product Defect and Manufacturing Defect (New 
Sec. 514.3(g))

    (Comment 12) Many comments expressed concern that the proposed 
definitions for ``product defect'' and ``manufacturing defect'' were 
too broad because, under the definitions, FDA would require reporting 
of problems not associated with public health or animal safety.
    We agree. We revised the two definitions to limit their scope to 
problems associated with public health or animal safety. For example, 
we have removed the following language, ``observable or measurable 
deviation * * * from the typical physical and chemical characteristics 
expected for the animal drug product and its container'' to prevent 
inclusion of factors that may affect physical appearance, but not 
public health or animal safety. For clarity, the two definitions have 
been combined in a single definition in new Sec. 514.3(g). The revised 
definition also contains examples of product and manufacturing defects.
    (Comment 13) One comment stated that the definition of ``product 
defect'' should be revised to specify only a situation when there is a 
confirmed deviation from standards in order to preclude submission of 
many reports that may prove to be unnecessary.
    We disagree that the definition of suspected product defects should 
be revised to include only confirmed deviation from standards. We 
believe that if an applicant/nonapplicant had to confirm the deviation, 
it would be difficult for the applicant/nonapplicant to report such a 
defect within 3 working days of first becoming aware that a defect may 
exist, as required under new Sec. 514.80(b)(1). However, we have 
revised the definitions of product defect and manufacturing defect to 
limit their scope (see comment 12 of this document). We have also 
narrowed the reporting requirement under Sec. 514.80(b)(1) so that only 
those product and manufacturing defects that may result in serious 
adverse drug events must be reported.
    During its consideration of this comment, we recognized a source of 
potential confusion in the proposed rule that is related to the issue 
raised by the comment. Specifically, ``manufacturing defect'' was 
defined in proposed Sec. 514.80(b)(7) as ``the manufacturing process is 
the cause of a product defect which is determined after investigation 
of a product defect complaint or a routine quality control procedure.'' 
(Emphasis added). We did not intend for this definition to alter the 
requirement that manufacturing defects be reported to FDA within 3 
working days of first becoming aware that such a defect may exist. To 
eliminate this potential confusion, we removed the phrase ``which is 
determined after investigation of a product defect complaint or a 
routine quality control procedure'' from the interim final rule's 
definition of ``product defect/manufacturing defect'' in new 
Sec. 514.3(g).
    (Comment 14) Some comments suggested that the phrase ``or from the 
typical physical and chemical characteristics expected for the animal 
drug product and its container,'' which appears in the proposed rule's 
definition of ``product defect,'' should be modified or deleted because 
it makes the definition too broad.
    We agree that the phrase makes the definition too broad. We removed 
the phrase in this interim final rule.
    (Comment 15) One comment argued that the proposed definition of 
``manufacturing defect'' should be changed to specify distributed 
products only because the proposed definition would include reporting 
of all quality control or procedure problems.
    FDA agrees that only those manufacturing defects that pertain to 
distributed products need be reported. The revised definition in new 
Sec. 514.3(g) makes this clear by referring to ``distributed'' 
products.

H. Records to be Maintained (New Sec. 514.80(e))

    (Comment 16) Some comments challenged the proposed 10-year 
retention period for records of all information concerning experience 
with approved new animal drugs. They argued that a 10-year retention 
period is unnecessary and burdensome. They suggested that the retention 
time be reduced to 1 or 2 years.
    FDA agrees that 10 years may be an unnecessarily long time to 
retain these records of all information. Accordingly, the agency has 
amended the record retention period from 10 to 5 years. New 
Sec. 514.80(e) requires retention of records of all information for 5 
years after the date of submission. FDA believes that a 5-year 
retention period is adequate and necessary to ensure that records exist 
for a sufficient time to permit us to evaluate events that occur at 
limited frequency.

[[Page 5050]]

I. Reporting Requirements (New Sec. 514.80(b))

    (Comment 17) Some comments misrepresented our intent regarding 
reporting requirements, indicating that we had not clearly stated those 
requirements in the proposed rule. As a result of these comments, we 
reorganized and revised the reporting requirements to clarify reporting 
obligations. New Sec. 514.80(b) does not add any significant new 
reporting requirements to those contained in the proposed rule. In 
fact, we removed or modified some of the proposed requirements to 
reduce the regulatory burden. A discussion of the specific changes that 
we made follows.

J. NADA-field Alert Report (New Sec. 514.80(b)(1))

    (Comment 18) One comment suggested that the requirement for 
reporting product and manufacturing defects should be limited to 
significant problems relevant to the drug's safety or efficacy.
    FDA agrees and has revised the reporting requirements in new 
Sec. 514.80(b)(1) so that only those product and manufacturing defects 
that may result in serious adverse drug events must be reported.
    (Comment 19) Some comments expressed a concern that the proposed 
rule would require duplicate reporting of manufacturing defects to 
FDA's district offices and Center for Veterinary Medicine (CVM).
    We did not intend to require duplicate reporting. The agency 
believes this was clear under proposed Sec. 514.80(d)(1), which stated 
that reports should be submitted ``to the FDA district office that is 
responsible for the facility involved.'' Thus, we are largely retaining 
this language. However, because some areas of the United States are 
covered by a local FDA resident post rather than a district office, the 
agency is modifying the interim final rule to reflect this. New 
Sec. 514.80(b)(1) states that ``[t]he applicant * * * must submit the 
report to the appropriate FDA district office or local FDA resident 
post within 3 working days of first becoming aware that a defect may 
exist.'' To further clarify where specific reports must be sent, we 
have added new Sec. 514.80(g) Mailing addresses to this interim final 
rule.
    (Comment 20) One comment suggested extending the time required for 
submitting the proposed NADA field alert report from 3 to 10 days.
    We believe that 3 working days are sufficient time to investigate 
the existence of a reportable event and make an initial report. Thus, 
we have retained this timeframe for 3-day NADA/ANADA field alert 
reports in new Sec. 514.80(b)(1). The agency notes that a complete 
written report is not required within the 3-day period. If, as 
specified in Sec. 514.80(b)(1), the information is provided by 
telephone or other telecommunication means within 3 days, followed by 
prompt (within a timeframe agreed upon at the time of the initial 
telecommunication) written followup on Form FDA 1932 ``Veterinary 
Adverse Drug Reaction, Lack of Effectiveness, Product Defect Report,'' 
FDA will consider the 3-day requirement to have been met.

K. Fifteen-Day Alert Reports (New Sec. 514.80(b)(2))

    (Comment 21) Several comments interpreted proposed 
Sec. 514.80(d)(2)(ii) as requiring repeated followup reports at 15-day 
intervals. These comments questioned the need for such followup and 
proposed a single followup once all the information was collected 
within 15 days or after collection of the information.
    The intent of the regulation is not to require multiple followup 
reports. We believe that most adverse drug experiences can be 
documented with either a single initial report or an initial report and 
a followup report if significant new information is received. To 
clarify this intent, Sec. 514.80(b)(2)(ii) of the interim final rule 
has been revised to read: ``* * *[if] this investigation reveals 
significant new information, a followup report must be submitted within 
15 days of receiving such information.'' A 3-month period is designated 
as the reasonable time needed to obtain such information. If additional 
information is sought but not obtained within 3 months of the initial 
report, a followup report is required describing the steps taken and 
why additional information was not obtained.
    (Comment 22) Proposed Sec. 514.80(d)(2) required that the initial 
15-day alert report be submitted using Form FDA 1932. One comment 
suggested that the Form FDA 1932 be submitted only at the conclusion of 
the investigation of the adverse drug experience. The comment suggested 
that the initial report could be less formal.
    We disagree with these suggestions. A standardized reporting format 
is essential for the efficient collection and processing of useful 
data. Thus, FDA has retained the required use of the Form FDA 1932 for 
the 15-day NADA/ANADA alert report in this interim final rule.
    (Comment 23) Several comments suggested that 15-day alert reports 
of adverse drug experiences be limited to events judged to be ``drug-
related'' by the applicant.
    We disagree with this concept. For FDA to determine drug-related 
effect, applicants must submit all reports of adverse drug experience 
so that the agency can evaluate the data in an unbiased manner. FDA 
maintains a computer data base of reported information. The data base 
is evaluated for trends or patterns of reports, and the trends are 
further investigated. Limiting reporting to ``drug-related'' events 
could hamper the discovery of uncommon or unexpected adverse drug 
experiences.
    To alleviate concerns that reporting automatically implicates the 
drug, we added new Sec. 514.80(i). This section provides that the 
adverse drug experience report ``will be without prejudice and does not 
necessarily reflect a conclusion that the report or information 
constitutes an admission that the drug caused or contributed to an 
adverse event.''

L. Periodic Adverse Drug Experience Reports (New Sec. 514.80(b)(4))

    (Comment 24) Several comments criticized proposed 
Sec. 514.80(d)(3), asserting that the proposed requirements for 
periodic drug experience reports are inappropriate, unnecessary, and 
burdensome in requiring quarterly reports for 3 years. Two comments 
recommended 6-month reports for 2 years.
    We agree with many of the comments and revised the provisions 
regarding periodic drug experience reports. We have combined the 
periodic adverse drug experience report requirements with annual 
reporting requirements into new section, Sec. 514.80(b)(4). The 
frequency of reporting for new approvals has been changed from the 
proposed schedule of ``quarterly intervals for 3 years from the date of 
approval and annually thereafter'' (as it appeared in proposed 
Sec. 514.80(d)(3)) to ``every 6 months for the first 2 years after 
approval of an NADA or ANADA, and yearly thereafter.'' (See new 
Sec. 514.80(b)(4).) In light of this change, we wish to clarify the 
reporting requirement for the periodic drug experience reports. We are 
requiring that these periodic drug experience reports contain data and 
information for the full reporting period. To facilitate this reporting 
requirement, we will allow sponsors to file 6-month periodic drug 
experience reports within 30 days after the end of the 6-month 
reporting period. With regard to the yearly periodic drug experience 
report, these

[[Page 5051]]

must be submitted within 60 days of the anniversary date of the 
approval of the NADA or ANADA.
    FDA added provisions in new Sec. 514.80(b)(4) that allow applicants 
to petition FDA to change the date of submission of yearly periodic 
drug experience reports or the frequency of reporting to intervals 
greater than annually. This is intended to increase flexibility and to 
reduce the reporting burden for specific NADAs and ANADAs. FDA believes 
that any burden for the third semiannual report will be offset by the 
provision in new Sec. 514.80(b)(4) that allows applicants to petition 
for decreased reporting frequency.

M. Proposed Sec. 514.80(d)(4): Annual Report (Interim Final Included in 
Sec. 514.80(b)(4))

    (Comment 25) Two comments noted that the phrase ``quantities 
distributed for foreign use'' in proposed Sec. 514.80(d)(4)(I) is 
unclear, and that the collection of the data would be unreliable and 
difficult to obtain.
    The phrase, which is now in new Sec. 514.80(b)(4)(i), has been 
revised to read ``quantities distributed domestically and quantities 
exported.'' We believe that the data are obtainable (currently, CVM 
receives such data from applicants) and, if properly collected, should 
be reliable. The data will be useful in CVM's postmarketing 
surveillance activities, such as the adverse drug experience program.
    (Comment 26) Four comments objected to the requirement in proposed 
Sec. 514.80(d)(4)(ii) that applicants provide a summary of any changes 
in the labeling. Comments argued that FDA already has this information 
on file.
    We believe that this requirement does not impose a significant new 
reporting burden, yet provides us with very useful information. The 
requirement is necessary to ensure that all labeling changes, including 
those recently made or not previously reported, are documented. By 
providing a summary of any changes in the labeling, applicants will 
facilitate CVM's review of periodic drug experience reports. Therefore, 
we retained the requirement in new Sec. 514.80(b)(4)(ii).
    (Comment 27) Several comments questioned the need for providing the 
date of implementation of manufacturing and control changes, required 
under proposed Sec. 514.80(d)(4)(iv). The comments described the 
requirement as an unnecessary paperwork burden on both industry and 
Government. One comment noted that the requirement was redundant 
because ``a chronological list of changes is available upon field 
inspection.''
    We disagree with these comments. The date when a change is 
implemented is important to identify the production batches that may be 
affected by the change. This is important for various reasons, 
including allowing reviewers to compare data generated at different 
times to determine if there are any changes or trends in product 
quality. However, section 116 of the Food and Drug Administration 
Modernization Act of 1997 (FDAMA) (21 U.S.C. 356a) describes reporting 
procedures and requirements for making major and other manufacturing 
changes to an approved application. Under FDAMA, we proposed to revise 
Sec. 514.8 (21 CFR 514.8), the provisions for supplemental applications 
for changes in the manufacturing of animal drugs, and specify the 
reporting requirements for manufacturing changes. (See 64 FR 53281, 
October 1, 1999.) Therefore, we removed the requirement described in 
proposed Sec. 514.80(d)(4)(iv) from this interim final rule.
    (Comment 28) Proposed Sec. 514.80(d)(4)(v)(C) required applicants 
to submit descriptions of completed clinical trials conducted by or 
known to the applicant. Some comments questioned whether this 
requirement would result in possible duplicate reporting of clinical 
trial information or adverse drug experiences associated with an 
investigational new animal drug. Also, the difference between the terms 
``completed'' and ``concluded'' was questioned in terms of when the 
study was to be reported to FDA. Proposed Sec. 514.80(d)(4)(v)(C) 
stated: ``A study is considered completed no later than 1 year after it 
is concluded.''
    We did not intend to require duplicate reporting. To make this 
explicit, we renamed the section ``Nonclinical laboratory studies and 
clinical data not previously reported,'' in new Sec. 514.80(b)(4)(iii). 
We included the phrase ``not previously reported'' in the title to 
clarify that duplicate reporting is not required. To eliminate 
confusion over the difference between ``completed'' and ``concluded,'' 
new Sec. 514.80(b)(4)(iii)(C) now states that ``a study must be 
submitted no later than 1 year after completion of research.''

N. Advertisements and Promotional Labeling (New Sec. 514.80(b)(5)(ii))

    (Comment 29) Several comments suggested that the requirements 
regarding submission of advertisements and promotional labeling in 
Sec. 510.300 were adequate. These comments further suggested that FDA 
should retain these requirements rather than adopting the new 
requirement in proposed Sec. 514.80(d)(5)(I). In addition, the comments 
challenged as unnecessary and burdensome the requirement that a copy of 
the product labeling be included in the submission.
    The agency believes that the language in new Sec. 514.80(b)(5)(ii) 
is an improvement over Sec. 510.300 because it clarifies and delineates 
the requirements for advertisements and promotional labeling for both 
prescription and over-the-counter drugs. However, FDA agrees that 
samples of a product's current labeling need not accompany each 
submission of promotional material. Accordingly, we removed this 
requirement from the regulation.

O. Distributor Statements and Labeling (New Sec. 514.80(b)(5)(iii))

    (Comment 30) Comments asserted that the timing of submission of the 
distributor statement and labeling as established under proposed 
Sec. 514.80(d)(5)(ii) was unclear because the preamble to the proposed 
rule suggested submission with the annual report, but the proposed rule 
required submission ``[a]t the time of initial distribution.''
    We clarified the timing of submission in the interim final rule. In 
new Sec. 514.80(b)(5)(iii), the distributor's statement and samples of 
labeling are to be submitted as a special drug experience report ``at 
the time of initial distribution of a new animal drug product by a 
distributor.''
    (Comment 31) Comments also questioned the meaning of the term 
``own-label (private label) distributor'' as it appeared in proposed 
Sec. 514.80(d)(5)(ii).
    We agree that the proposed language was unclear. We removed the 
phrase ``own-label (private label).'' The wording in new 
Sec. 514.80(b)(5)(iii)(A) reads, ``distributor's current product 
labeling.''
    (Comment 32) One comment asserted that the information required in 
distributor statements are business arrangements which should be kept 
on file by applicants and not be submitted to FDA.
    We disagree with this comment. The distributor statements are kept 
on file at FDA to provide cross-reference information for the drug 
listing process. The statements may also be important to us during an 
establishment inspection.

P. Statements of NADA Approval Status

    (Comment 33) Proposed Sec. 514.80(d)(5)(iii) codified the reporting 
requirements that applicants needed to comply with before they could 
add a statement of NADA approval status to

[[Page 5052]]

the product labeling. Before the enactment of FDAMA, the act expressly 
prohibited the use of approval status statements on the labeling of 
human drugs under section 301(l) of the act (21 U.S.C. 331(l)), but did 
not prohibit the use of such statements on new animal drug labeling. 
Section 421 of FDAMA struck section 301(l) from the act, thereby 
lifting the prohibition for adding such statements to human drug 
labeling. Because the agency has decided that it will implement this 
revision of the act by providing uniform guidance concerning product 
approval status statements for both human and animal products, we 
determined that it would be inappropriate to retain proposed 
Sec. 514.80(d)(5)(iii) in this interim final rule.

Q. Special Reports (New Sec. 514.80(b)(5)(i))

    (Comment 34) Proposed Sec. 514.80(d)(5)(iv) provided that ``[u]pon 
written request, FDA may require that the applicant submit the reports 
required under this section at different times than those stated.'' One 
comment suggested that FDA should have retained Sec. 510.300(b)(5) 
rather than adopting proposed Sec. 514.80(d)(5)(iv). This comment 
interpreted the language in Sec. 510.300(b)(5) as ensuring that special 
reports are based on a ``mutually agreed upon need and not a mere 
increase in frequency in reporting.''
    We do not interpret the language of Sec. 510.300(b)(5) as having 
provided a means of ``mutually agreeing upon'' some kind of need for a 
report. Moreover, we believe it is neither necessary nor practical to 
ensure that special reports are based on a ``mutually agreed upon 
need.'' Proposed Sec. 514.80(d)(5)(iv) was not intended to 
unnecessarily increase the frequency of reporting. Rather, this 
proposed section provides us with a means of obtaining reports in 
situations where we believe that it is in the interest of public health 
to require a different timeframe for the submission of reports required 
in this regulation. To further this goal, we are adopting the following 
language for the interim final rule (new Sec. 514.80(b)(5)(i)): ``Upon 
written request, FDA may require that the applicant submit a report 
required under Sec. 514.80 at different times or more frequently than 
the timeframes stated in Sec. 514.80.''

R. General Requirements (New Sec. 514.80(c))

    (Comment 35) Several comments requested clarification of proposed 
Sec. 514.80(e)(1) which states: ``If a report refers to more than one 
animal drug marketed by an applicant, the applicant shall submit the 
report to the application for each animal drug listed in the report. 
The report is required to identify all the applications to which the 
report applies.'' Comments questioned whether this was applicable to 
combination drug products and whether FDA intended the applicant to 
file these reports with all dosage forms of the drug or just with the 
dosage form involved in the adverse experience report.
    This section was intended to refer to periodic reporting 
requirements when an applicant has more than one NADA or ANADA 
containing a particular active ingredient. FDA has replaced the 
language proposed in Sec. 514.80(e)(1) with language almost identical 
to that contained in Sec. 510.300(b)(4)(ii). FDA has redesignated the 
general requirements section as Sec. 514.80(c) in the interim final 
rule, and has further clarified the requirements needed to implement 
this section. The clarification provided for in the interim final of 
Sec. 514.80(c)(1) through (c)(4) reflects the current reporting 
practice. If applicable, the applicant must do the following: (1) State 
when a report applies to multiple applications and identify all related 
applications; (2) ensure that the primary application contains a list 
of all related applications; (3) submit a completed Form FDA 2301, 
``Transmittal of Periodic Reports and Promotional Materials for New 
Animal Drugs,'' to the primary application, and to each related 
application that references the primary application and corresponding 
submission date; and (4) if there is information that is unique to a 
particular application, the information must be submitted in the report 
for that particular NADA and/or ANADA.

S. General Requirements--[Reports of Adverse Drug Experiences in 
Published Literature] (New Sec. 514.80(b)(4)(iv)(B))

    (Comment 36) Several comments questioned the scope of the published 
literature that needed to be provided to FDA. The comments asserted 
that only publications from current scientific journals (excluding 
those listed in 21 CFR 510.95) and only substantive articles should be 
required. The comments stated that obscure foreign journals with 
translations may require extended time periods to obtain. Section 
314.80(d)(1) and (d)(2) of the human drug regulations were mentioned as 
examples of appropriate limitations.
    We believe that the scope of published literature on reports of 
adverse drug experiences should be kept broad. In recent years, 
extensive searches of literature data bases have become quicker, more 
practical, and more economical to perform. If the agency were to narrow 
the scope of these searches, potentially valuable information might not 
be submitted. However, in an effort to reduce the burden of this 
requirement upon applicants, the agency has revised the requirement. 
Under proposed Sec. 514.80(e)(2), applicants would have been required 
to submit actual copies of all published articles. We revised this 
requirement (new Sec. 514.80(b)(4)(iv)(B)) such that applicants 
generally need only include a bibliography of pertinent references in 
the report.
    (Comment 37) Several comments suggested that the requirement to 
provide photocopies of published articles was impractical because of 
copyright restrictions of publishers.
    We are now able to access abstracts and articles through electronic 
data bases via the Internet. This development has eliminated the need 
for applicants to include copies of abstracts or articles in each 
report. Thus, as stated above, proposed Sec. 514.80(e)(2) has been 
revised. Under the new Sec. 514.80(b)(4)(iv)(B), an applicant will be 
required to provide a full text copy of a publication only upon FDA's 
request.

T. General Requirements--Reports of Adverse Drug Experiences in 
Postapproval Studies (New Sec. 514.80(b)(4)(iv)(C))

    (Comment 38) Two comments suggested that reporting of adverse 
experiences in postapproval studies as required in proposed 
Sec. 514.80(e)(3) was redundant and might result in duplicate 
reporting.
    In response to these comments, the language in new 
Sec. 514.80(b)(4)(iv)(C) has been changed to specify ``[r]eports of 
adverse drug experiences in studies or trials not previously reported 
either individually or as part of an NADA/ANADA * * *'' (Emphasis 
added).

U. Reporting Forms (New Sec. 514.80(d))

    (Comment 39) One comment stated that Form FDA 1932 is poorly suited 
for reports of product defects or human exposure to animal drugs. The 
suggestion was made that FDA modify the form or allow alternative 
reporting formats.
    We believe that Form FDA 1932 and Form FDA 2301 are appropriate 
vehicles for reporting. Thus, the agency is retaining the requirement 
that these forms be used where designated in the interim final rule.

[[Page 5053]]

V. Withdrawal of Approval (New Sec. 514.80(h))

    (Comment 40) A comment suggested that FDA should retain the 
provisions in Sec. 510.300(d) rather than adopting proposed 
Sec. 514.80(h), because previous Sec. 514.300(d) included an 
opportunity for a hearing. Although the agency disagrees that language 
in proposed Sec. 514.80(h) should be replaced with the language 
previously found in Sec. 514.300(d), the agency has rewritten proposed 
Sec. 514.80(h) for clarity. As part of this revision, the agency has 
added the following: ``If FDA determines that withdrawal of the 
approval is necessary, the agency shall give the applicant notice and 
opportunity for hearing, as provided in Sec. 514.200, on the question 
of whether to withdraw approval of the application.''

W. Records and Reports Concerning Experience With Animal Feeds Bearing 
or Containing New Animal Drugs for Which an Approved Application is in 
Effect

    FDA received several comments on the proposed regulation concerning 
the portion of the regulation dealing with MFAs. However, the ADAA 
amended the statutory provisions in the act regarding medicated feeds. 
Type A medicated articles are new animal drugs that may be used to make 
medicated feeds. Feed mills use Type A medicated articles to make 
medicated feeds. Prior to the passage of the ADAA, sponsors were 
required to obtain approval of NADAs for Type A medicated articles, and 
feed mills that made medicated feeds were required to obtain approval 
of an MFA for each medicated feed manufactured at each site before they 
could legally manufacture the medicated feed. The ADAA eliminated this 
requirement regarding MFAs for feed mills, but not the requirement for 
sponsors to obtain approval of NADAs for Type A medicated articles.
    Revisions to the MFA regulations to reflect the provisions of ADAA 
were the subject of a final rule that published in the Federal Register 
of November 19, 1999 (64 FR 63195). Because of these revisions, the 
agency has removed the requirements for MFAs from the final rule. 
Proposed Sec. 514.81 described the records and reports requirements for 
holders of MFAs. There are no longer holders of MFAs. However, the 
agency still needs information regarding approved Type A medicated 
articles incorporated in animal feeds. Under the final rule, this 
information is provided by the holder of the NADA for the Type A 
medicated feed, and, as stated in new Sec. 514.80(a)(4), the record and 
report requirements found in new Sec. 514.80(b)(1), (b)(2), and 
(b)(4)(iv) are applied to any approved Type A medicated article 
incorporated in animal feeds. The agency will address any remaining 
issues regarding records and reports for medicated feeds at a later 
date in a new proposed rule, if necessary.

X. Records and Reports Concerning Experience With New Animal Drugs From 
Manufacturers, Packers, Labelers, and Distributors Other Than the 
Applicant (New Sec. 514.80(b)(3))

    (Comment 42) Proposed Sec. 514.82 established requirements for 
records and reports concerning experience with new animal drugs from 
manufacturers, packers, labelers, and distributors other than the 
applicant. Several comments stated that requiring a nonapplicant to 
report to FDA is neither efficient nor necessary, because it would 
result in duplicate reporting. One comment stated that an applicant may 
be a subsidiary of a parent firm.
    We agree with these comments and have deleted the proposed section 
from the regulations. However, the agency has retained certain record 
and report requirements for nonapplicants (new Sec. 514.3(f)) in new 
Sec. 514.80(b). The interim final rule specifies under new 
Sec. 514.80(b)(3) that the nonapplicant is required to provide 
necessary information to the applicant. The applicant is required to 
report to FDA. The nonapplicant must retain certain records concerning 
events as provided in new Sec. 514.80(b)(3). The nonapplicant may 
choose to forward a copy of the report to FDA, but this action would be 
voluntary.

III. Conforming Amendments

    With the amendment of the animal drug regulations, certain 
revisions to 21 CFR parts 211, 226, 510, and 514 are required to 
conform to the designations in the amendments. Certain other provisions 
of part 510 and Sec. 514.8 are superseded by these regulations and are 
removed.

IV. Request for Comments

    Interested persons may submit to the Dockets Management Branch 
(address above) written or electronic comments on new information 
regarding this interim final rule by April 5, 2002. 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 Dockets Management Branch between 9 a.m. and 4 p.m., Monday 
through Friday. The agency believes it is in the public interest to 
have the regulations in place while, at the same time, it solicits 
public comments on new issues. The agency will not consider any 
comments that have been previously considered during this rulemaking.

V. Environmental Impact

    FDA has determined under 21 CFR 25.30(h) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VI. Federalism

    FDA has analyzed this interim final rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the rule does not contain policies that have substantial direct effects 
on the States, on the relationship between the National Government and 
the States, or on the distribution of power and responsibilities among 
the various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the order and, consequently, a federalism 
summary impact statement is not required.

VII. Analysis of Impacts

    FDA has examined the impacts of the interim final rule under 
Executive Order 12866 and has determined that it does not constitute an 
economically significant rule, as defined in the Executive order. FDA 
also certifies in accordance with the Regulatory Flexibility Act (5 
U.S.C. 601-612) that this rule will not have a significant economic 
impact on a substantial number of small entities, and therefore, a 
regulatory flexibility analysis is not required. Further, since this 
rule will not impose any mandates on other governmental entities and 
will result in the expenditure of less than $100 million by the private 
sector, FDA does not need to prepare additional analyses under the 
Unfunded Mandates Reform Act.
    The regulation is intended to clarify and simplify recordkeeping 
requirements while improving the protection of public and animal 
health. The revisions in the reporting requirements are expected to 
provide savings through lower recordkeeping costs in some areas while 
imposing small cost increases due to requirements

[[Page 5054]]

for recordkeeping of more useful information.
    In the rule, the term ``applicant'' is limited to the holder of an 
approved application (NADA or ANADA) and does not include every firm 
whose name appears on product labeling, as the regulations previously 
provided. A nonapplicant is required to send copies of necessary 
information to the applicant who would then combine all information 
received, whether from one or several sources, and submit a single 
report to FDA. This change would reduce paperwork requirements because 
firms would be required to submit fewer reports. Also, those reports 
should provide for a more comprehensive reporting of all required 
information.
    The current requirement for adverse drug experience reports to be 
submitted by distributors under proposed Sec. 514.82 is retained under 
the interim final rule in Sec. 514.80(b)(3) in nonapplicant reporting. 
The requirement for any firm involved in the manufacturing, processing, 
packing, labeling, or distributing of a new animal drug product other 
than the applicant (the nonapplicant) to report adverse experiences 
either to FDA or to the applicant is a restatement of the previous 
provisions of Sec. 510.300(f) that applies to a small number of firms 
that would not routinely be expected to receive such information. The 
restatement is intended to clearly state that any such information 
received is required to be reported to FDA, either directly or through 
the applicant. However, only one party would be required to file the 
report.
    The revised regulations amend the language of the regulations to 
clarify current practices. The conformity of reporting requirements for 
animal drugs and human drugs may simplify the process for firms that 
manufacture both kinds of products. No added costs are expected for 
those firms who only manufacture new animal drug products.
    In the past, FDA has required that records and reports be retained 
for an indefinite period. The proposed rule provided for a retention 
period of 10 years. FDA has changed this requirement to 5 years for all 
information, in response to industry comments. This would provide an 
additional opportunity for savings compared to the proposed rule. Since 
the current average length of time which records are kept is unknown, 
it is possible that there will be a small net cost due to this 
provision, even though the reporting requirements are clarified for 
easier compliance and administration.
    The previously existing regulation required reports concerning 
newly approved NADAs and ANADAs every 6 months for the first year and 
annually thereafter. The proposed rule for records and reports would 
have required submission of such reports at quarterly intervals for 3 
years following approval. FDA agrees with comments from industry that 
the proposed rule's requirement of reports at quarterly intervals for 3 
years following approval was unnecessary, and the agency has decreased 
the reporting requirements in the interim final rule. The interim final 
rule requires reports of adverse drug experiences to be submitted every 
6 months for 2 years and annually thereafter.
    The net change from the previous regulation requires one additional 
report in the second year. FDA estimates that it approves 30 NADAs 
annually. FDA estimates that 13.6 hours are required to establish and 
maintain the drug experience data, as well as write the report. Total 
hours required for this provision are estimated at 408. At a middle 
manager's estimated total wage rate of $35 per hour, this provision 
would cost $14,280 annually. Moreover, applicants may petition for 
lengthier report intervals. FDA will provide for reporting at intervals 
longer than 1 year when justified based on current experience or 
manufacturing and marketing status. The expected number of petitions 
for reporting at intervals greater than 1 year is difficult to estimate 
because it depends on the extent to which each individual company 
wishes to qualify for this provision. The net result of these two 
provisions may be either a very small cost or savings to each firm.
    The interim final rule requires applicants to periodically review 
the incidence of adverse drug experiences and report any significant 
increase in the frequency to FDA as soon as possible or within 15 
working days of determining a significant increase in frequency exists. 
FDA expects to receive very few of these each year and estimates the 
annual number at 1 to 20. These reports would not be expected to take 
more than 1 to 2 hours of a manager's time, and the high-end estimated 
cost would be $1,400 annually. Periodic review of adverse drug 
experience reports, although on a less formal basis, is already 
understood to be normal business practice.
    The net costs and benefits of this interim final rule, though 
indeterminate, are expected to be modest. FDA concludes that the 
impacts of the interim final rule do not qualify it as an economically 
significant rule as defined under Executive Order 12866.
    The Regulatory Flexibility Act, as amended (5 U.S.C. 601-612), 
allows for a waiver of the regulatory flexibility analysis if an agency 
certifies there will not be a significant impact on a substantial 
number of small entities as a result of a rule, as well as provides the 
factual basis for such a certification. The Small Business 
Administration definition of a small business in this industry category 
is limited to those firms with less than 750 employees. It is expected 
that a substantial number of the firms which will be subject to the new 
recordkeeping and reporting requirements will meet the definition of 
small businesses. FDA estimates that from 1 to 13 of the approximately 
30 NADA and ANADA approvals in 1999 may have been from small 
businesses. Using the upper end of this range, about 42 percent of the 
firms receiving approval annually would be subject to the new 
recordkeeping and reporting requirements. Although these firms 
constitute a substantial number of firms being granted an approval each 
year, this proposal is not expected to have a significant economic 
impact on these firms, because the interim final rule is intended to 
simplify and clarify current recordkeeping and reporting requirements. 
The net costs and benefits on each small firm are expected to be 
modest. Accordingly, FDA certifies in accordance with the Regulatory 
Flexibility Act (5 U.S.C. 601-612) that this rule will not have a 
significant economic impact on a substantial number of small entities, 
and therefore, a regulatory flexibility analysis is not required.

VIII. Paperwork Reduction Act of 1995

    This interim final rule contains information collection provisions 
that are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). A description of these provisions is given below. Included is 
the time for reviewing instructions, searching existing data sources, 
gathering and maintaining the data needed, and completing and reviewing 
each collection of information.
    Title: Records and Reports Concerning Experience With Approved New 
Animal Drugs
    Description: This interim final rule amends the provisions of the 
animal drug regulations concerning requirements for recordkeeping and 
reports of adverse experiences and other information relating to 
approved new animal drugs. The information

[[Page 5055]]

contained in the reports required by this rule enables FDA to monitor 
the use of new animal drugs after approval and to ensure their 
continued safety and efficacy. The reporting requirements include: A 
report that provides information on product and manufacturing defects 
that may result in serious adverse drug events (new Sec. 514.80(b)(1)); 
a report that provides information on serious, unexpected adverse drug 
events and a followup report on such events (new Sec. 514.80(b)(2)); a 
summary report of increased frequency of adverse drug experiences (new 
Sec. 514.80(b)(2)(iii)); a report from nonapplicants, such as 
distributors, to applicants providing information on adverse drug 
experiences (new Sec. 514.80(b)(3)); a periodic report with information 
on distribution, labeling, manufacturing or controls changes, new 
laboratory studies, and all adverse events in the reporting period (new 
Sec. 514.80(b)(4)); and other reports that include special drug 
experience report; reports for advertising and promotional material, 
and reports for distributor statements (new Sec. 514.80(b)(5)). These 
reports must be kept for 5 years (new Sec. 514.80(e)).
    The interim final rule strengthens the current reporting system by 
requiring periodic reports every 6 months for the first 2 years 
following initial approval of an application rather than just for the 
first year following initial approval. The increased burden on 
applicants amounts to one additional periodic report. While greater 
than the reporting burden in the previous rule, this burden is less 
than that of the proposed rule which would have required quarterly 
periodic reports for 3 years following initial approval.
    The reporting burden of the proposed rule has been reduced further 
in other ways. In the interim final rule, the report pertaining to 
product and manufacturing defects must include only information on 
defects ``that may result in serious adverse drug events'' (new 
Sec. 514.80(b)(1)) rather than information on all manufacturing 
defects, as in the proposed rule. Additionally, the proposed rule 
required a periodic adverse drug experience report and an annual 
report, whereas the interim final rule has combined these reports into 
a single periodic drug experience report (new Sec. 514.80(b)(4)). The 
interim final rule also reduces the reporting requirements of the 
proposed rule by eliminating proposed Sec. 514.82, which required 
records and reports from manufacturers, packers, labelers, and 
distributors other than the applicant. The recordkeeping requirements 
of the proposed rule have also been reduced in the interim final rule 
by changing the required period of time records must be kept from 10 to 
5 years (new Sec. 514.80(e)).
    All periodic reports must be submitted with Form FDA 2301, 
``Transmittal of Periodic Reports and Promotional Materials for New 
Animal Drugs'' (OMB Control No. 0910-0012). Adverse drug experience 
reports must be submitted on Form FDA 1932, ``Veterinary Adverse Drug 
Reaction, Lack of Effectiveness, Product Defect Report'' (OMB Control 
No. 0910-0012).
    Description of Respondents: Applicant respondents are sponsors of 
approved NADAs and ANADAs. Nonapplicant respondents are those, other 
than the applicant, involved in manufacturing, processing, packing, 
labeling, or distributing new animal drugs.
    Although the proposed rule of December 17, 1991 (56 FR 65581), 
provided a 60-day comment period under the PRA of 1980 and this interim 
final rule responds to the comments received; FDA is providing an 
additional opportunity for public comment under the PRA of 1995, which 
became effective after the publication of the proposed rule and applies 
to this interim final rule. Therefore, FDA now 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.
    At the close of the 60-day comment period, FDA will review the 
comments received, revise the information collection provisions as 
necessary, and submit these provisions to OMB for review and approval. 
FDA will publish a notice in the Federal Register when the information 
collection provisions are submitted to OMB and provide an opportunity 
for public comment to OMB at that time. Prior to the effective date of 
this interim final rule, FDA will publish a notice in the Federal 
Register of OMB's decision to approve, modify, or disapprove the 
information collection provisions. An agency may not conduct or 
sponsor, and a person is not required to respond to, a collection of 
information unless it displays a valid OMB control number.

                    RECORDS AND REPORTS CONCERNING EXPERIENCE WITH APPROVED NEW ANIMAL DRUGS
                                 Table 2.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
21 CFR Section/Title/FDA        No. of        Annual Frequency      Total Annual      Hours per
        Form No.             Respondents        per Response         Responses        Response     Total Hours
----------------------------------------------------------------------------------------------------------------
514.80(b)(2)(i)/Original          190                 55.26     12,283                   1       12,283
 15-Day Alert Report/
 Form FDA 1932
----------------------------------------------------------------------------------------------------------------
514.80(b)(1)/3-Day Field          190                  0.32     95                       1       95
 Alert Report/ Form FDA
 1932
----------------------------------------------------------------------------------------------------------------
514.80(b)(2)(ii)/                 190                 17.90     6,007                    1       6,007
 Followup 15-Day Alert
 Report/Form FDA 1932
----------------------------------------------------------------------------------------------------------------
514.80(b)(2)(iii)/                190                  1.58     300                      2       300
 Increased Frequency 15-
 Day Alert Report
----------------------------------------------------------------------------------------------------------------
514.80(b)(3)/                     340                  2.94     1,000                    1       1,000
 Nonapplicant Report/
 Form FDA 1932
----------------------------------------------------------------------------------------------------------------
514.80(b)(4)/Periodic             190                  7.11     1,226                   11       13,486
 Drug Experience Report/
 Form FDA 2301, and
 514.80(c) Multiple
 Applications\2\
----------------------------------------------------------------------------------------------------------------

[[Page 5056]]

 
514.80(b)(5)(i)/Special           190                  0.13     25                       2       50
 Drug Experience Report/
 Form FDA 2301
----------------------------------------------------------------------------------------------------------------
514.80(b)(5)(ii)/                 190                  2.11     772                      2       1,544
 Advertising and
 Promotional Materials
 Report/ Form FDA 2301
----------------------------------------------------------------------------------------------------------------
514.80(b)(5)(iii)/                530                  0.14     56                       2       112
 Distributor's Statement
 Report/ Form FDA 2301
----------------------------------------------------------------------------------------------------------------
Total                                                                                            34,877
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ The reporting burden for Sec.  514.80(b)(4)(iv)(A) is included in the reporting burden for Sec.
  514.80(b)(2)(i).


                               Table 3.--Estimated Annual Recordkeeping Burden\1\
----------------------------------------------------------------------------------------------------------------
                                No. of        Annual Frequency      Total Annual      Hours per
     21 CFR Section          Respondents        of Response          Responses        Response     Total Hours
----------------------------------------------------------------------------------------------------------------
514.80(e)\2\                      530                 28.22     19,385                   0.5     9,693
----------------------------------------------------------------------------------------------------------------
514.80(e)\3\                      530                  4.06     2,379                   10.35    24,623
----------------------------------------------------------------------------------------------------------------
Total                                                                                            34,316
----------------------------------------------------------------------------------------------------------------
\1\ Burden estimates were separated between Form FDA 1932 and Form FDA 2301 to reflect the difference in
  estimates for ``Hours per Respondent'' required.
\2\ Recordkeeping estimates for Secs.  514.80(b)(1), 514.80(b)(2)(i), 514.80(b)(2)(ii), and 514.80(b)(3); Form
  FDA 1932.
\3\ Recordkeeping estimates for Secs.  514.80(b)(2)(iii), 514.80(b)(4), 514.80(c), and 514.80(b)(5); Form FDA
  2301.

    Forms FDA 1932 and FDA 2301 for this collection of information are 
currently approved under OMB Control No. 0910-0012 and will not change 
due to implementation of this regulation. The reporting and 
recordkeeping burden estimates in this document are based on the 
submission of reports to the Division of Surveillance, Center for 
Veterinary Medicine. The total annual response numbers are based on the 
2000 fiscal year submission of reports to the Division of Surveillance, 
Center for Veterinary Medicine. The numbers in tables 2 and 3 are total 
burden associated with this regulation. Section 514.80(b)(2)(iii) and 
(b)(3) are new information collection requirements over the current 
requirements.

List of Subjects

21 CFR Part 211

    Drugs, Labeling, Laboratories, Packaging and containers, 
Prescription drugs, Reporting and recordkeeping requirements, 
Warehouses.

21 CFR Part 226

    Animal drugs, Animal feeds, Labeling, Packaging and containers, 
Reporting and recordkeeping requirements.

21 CFR Part 510

    Administrative practice and procedure, Animal drugs, Labeling, 
Reporting and recordkeeping requirements.

21 CFR Part 514

    Administrative practice and procedure, Animal drugs, Confidential 
business information, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
211, 226, 510, and 514 are amended as follows:

PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED 
PHARMACEUTICALS

    1. The authority citation for 21 CFR part 211 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374.


Sec. 211.198  [Amended]

    2. Section 211.198 Complaint files is amended in paragraph (a) in 
the last sentence by removing ``in accordance with Sec. 310.305 of this 
chapter'' and adding in its place ``as in Secs. 310.305 and 514.80 of 
this chapter.''

PART 226--CURRENT GOOD MANUFACTURING PRACTICE FOR TYPE A MEDICATED 
ARTICLES

    3. The authority citation for 21 CFR part 226 continues to read as 
follows:

    Authority: 21 U.S.C. 351, 352, 360b, 371, 374.


Sec. 226.1  [Amended]

    4. Section 226.1 is amended by redesignating the existing text as 
paragraph (a) and by adding paragraph (b) to read as follows:


Sec. 226.1  Current good manufacturing practice.

* * * * *
    (b) In addition to maintaining records and reports required in this 
part, Type A medicated articles requiring approved NADAs are subject to 
the requirements of Sec. 514.80 of this chapter.

PART 510--NEW ANIMAL DRUGS

    5. The authority citation for 21 CFR part 510 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 360b, 371, 379e.


Sec. 510.300  [Removed]

    6. Section 510.300 Records and reports concerning experience with 
new animal drugs for which an approved application is in effect is 
removed.

[[Page 5057]]

Sec. 510.302  [Removed]

    7. Section 510.302 Reporting forms is removed.

PART 514--NEW ANIMAL DRUG APPLICATIONS

    8. The authority citation for 21 CFR part 514 is revised to read as 
follows:

    Authority: 21 U.S.C. 360b, 371.
    9. Section 514.3 is added to subpart A to read as follows:


Sec. 514.3  Definitions.

    The definition and interpretation of terms contained in this 
section apply to those terms as used throughout subchapter E.
    (a) Adverse drug experience is any adverse event associated with 
the use of a new animal drug, whether or not considered to be drug 
related, and whether or not the new animal drug was used in accordance 
with the approved labeling (i.e., used according to label directions or 
used in an extralabel manner, including but not limited to different 
route of administration, different species, different indications, or 
other than labeled dosage). Adverse drug experience includes, but is 
not limited to:
    (1) An adverse event occurring in animals in the course of the use 
of an animal drug product by a veterinarian or by a livestock producer 
or other animal owner or caretaker.
    (2) Failure of a new animal drug to produce its expected 
pharmacological or clinical effect (lack of effectiveness).
    (3) An adverse event occurring in humans from exposure during 
manufacture, testing, handling, or use of a new animal drug.
    (b) ANADA is an abbreviated new animal drug application including 
all amendments and supplements.
    (c) Applicant is a person who owns a new animal drug application or 
ANADA.
    (d) Increased frequency of adverse drug experience is an increased 
rate of occurrence of a particular serious adverse drug event, expected 
or unexpected, after appropriate adjustment for drug exposure.
    (e) NADA is a new animal drug application including all amendments 
and supplements.
    (f) Nonapplicant is any person other than the applicant whose name 
appears on the label and who is engaged in manufacturing, packing, 
distribution, or labeling of the product.
    (g) Product defect/manufacturing defect is the deviation of a 
distributed product from the standards specified in the approved 
application, or any significant chemical, physical, or other change, or 
deterioration in the distributed drug product, including any microbial 
or chemical contamination. A manufacturing defect is a product defect 
caused or aggravated by a manufacturing or related process. A 
manufacturing defect may occur from a single event or from deficiencies 
inherent to the manufacturing process. These defects are generally 
associated with product contamination, product deterioration, 
manufacturing error, defective packaging, damage from disaster, or 
labeling error. For example, a labeling error may include any incident 
that causes a distributed product to be mistaken for, or its labeling 
applied to, another product.
    (h) Serious adverse drug experience is an adverse event that is 
fatal or life-threatening, requires professional intervention, or 
causes an abortion, stillbirth, infertility, congenital anomaly, 
prolonged or permanent disability, or disfigurement.
    (i) Unexpected adverse drug experience is an adverse event that is 
not listed in the current labeling for the new animal drug and includes 
any event that may be symptomatically and pathophysiologically related 
to an event listed on the labeling, but differs from the event because 
of greater severity or specificity. For example, under this definition 
hepatic necrosis would be unexpected if the labeling referred only to 
elevated hepatic enzymes or hepatitis.


Sec. 514.8  [Amended]

    10. Section 514.8 Supplemental new animal drug applications is 
amended in paragraph (a)(1) by removing ``Sec. 510.300(a) of this 
chapter'' and by adding in its place ``Sec. 514.80''; in paragraph 
(a)(5) by removing ``Sec. 510.300(b)(4) of this chapter'' and by adding 
in its place ``Sec. 514.80(b)(4)''; in paragraph (a)(5)(ix) by removing 
``Sec. 510.300(b)(1) of this chapter'' and by adding in its place 
``Sec. 514.80 (b)(1)''; and by revising paragraph (a)(6) to read as 
follows:
    (a) * * * 
    (6) Approval of a supplemental new animal drug application will not 
be required to provide for an additional distributor to distribute a 
drug which is the subject of an approved new animal drug application if 
the conditions described in Sec. 514.80(b)(5)(iii) are met before 
putting such a change into effect.


Sec. 514.11  [Amended]

    11. Section 514.11 Confidentiality of data and information in a new 
animal drug application file is amended in paragraph (a) by removing 
``510.300'' and adding in its place ``514.80''.


Sec. 514.15  [Amended]

    12. Section 514.15 Untrue statements in applications is amended in 
paragraph (b) by removing ``Sec. 510.300'' and adding in its place 
``Sec. 514.80''.
    13. Section 514.80 is added to subpart B to read as follows:


Sec. 514.80  Records and reports concerning experience with approved 
new animal drugs.

    The following table outlines the purpose for each paragraph of this 
section:

----------------------------------------------------------------------------------------------------------------
                                                                                                   Paragraph and
                                             Purpose                                                   Title
----------------------------------------------------------------------------------------------------------------
What information must be reported concerning approved NADAs or ANADAs?                             514.80(a)
                                                                                                    Applicabilit
                                                                                                    y
----------------------------------------------------------------------------------------------------------------
What authority does FDA have for requesting records and reports?                                   514.80(a)(1)
Who is required to establish, maintain, and report required information relating to experiences
 with a new animal drug?
Is information from foreign sources required?
----------------------------------------------------------------------------------------------------------------
What records must be established and maintained and what reports filed with FDA?                   514.80(a)(2)
----------------------------------------------------------------------------------------------------------------
What is FDA's purpose for requiring reports?                                                       514.80(a)(3)
----------------------------------------------------------------------------------------------------------------
Do applicants of Type A medicated articles have to establish, maintain and report information      514.80(a)(4)
 required under Sec.  514.80?
----------------------------------------------------------------------------------------------------------------

[[Page 5058]]

 
How do the requirements under Sec.  514.80 relate to current good manufacturing practices?         514.80(a)(5)
----------------------------------------------------------------------------------------------------------------
                                                                                                   514.80(b)
                                                                                                    Reporting
                                                                                                    Requirements
----------------------------------------------------------------------------------------------------------------
What are the requirements for reporting product/manufacturing defects?                             514.80(b)(1)
                                                                                                    Three-day
                                                                                                    NADA/ANADA
                                                                                                    Field Alert
                                                                                                    Report
----------------------------------------------------------------------------------------------------------------
                                                                                                   514.80(b)(2)
                                                                                                    Fifteen-day
                                                                                                    NADA/ANADA
                                                                                                    Alert Report
----------------------------------------------------------------------------------------------------------------
What are the requirements for reporting serious, unexpected and adverse drug experiences?          514.80(b)(2)(
                                                                                                    i) Initial
                                                                                                    Report
----------------------------------------------------------------------------------------------------------------
What are the requirements for followup reporting of serious, unexpected adverse drug experiences?  514.80(b)(2)(
                                                                                                    ii) Followup
                                                                                                    Report
----------------------------------------------------------------------------------------------------------------
What are the requirements for reporting increases in the frequency of serious, expected and        514.80(b)(2)(
 unexpected, and adverse drug experiences?                                                          iii) Summary
                                                                                                    Report of
                                                                                                    Increased
                                                                                                    Frequency of
                                                                                                    Adverse Drug
                                                                                                    Experience
----------------------------------------------------------------------------------------------------------------
What are the requirements for nonapplicants for reporting adverse drug experiences?                514.80(b)(3)
                                                                                                    Nonapplicant
                                                                                                    Report
----------------------------------------------------------------------------------------------------------------
What are the general requirements for submission of periodic drug experience reports, e.g., forms  514.80(b)(4)
 to be submitted, submission date and frequency, when is it to be submitted, how many copies?       Periodic
How do I petition to change the date of submission or frequency of submissions?                     Drug
                                                                                                    Experience
                                                                                                    Reports
----------------------------------------------------------------------------------------------------------------
What must be submitted in the periodic drug experience reports?                                    514.80(b)(4)(
                                                                                                    i) through
                                                                                                    (b)(4)(iv)
----------------------------------------------------------------------------------------------------------------
What distribution data must be submitted?                                                          514.80(b)(4)(
How should the distribution data be submitted?                                                      i)
                                                                                                    Distribution
                                                                                                    Data
----------------------------------------------------------------------------------------------------------------
What labeling materials should be submitted?                                                       514.80(b)(4)(
How do I report changes to the labeling materials since the last report?                            ii) Labeling
----------------------------------------------------------------------------------------------------------------
                                                                                                   514.80(b)(4)(
                                                                                                    iii)
                                                                                                    Nonclinical
                                                                                                    Laboratory
                                                                                                    Studies and
                                                                                                    Clinical
                                                                                                    Data Not
                                                                                                    Previously
                                                                                                    Reported
----------------------------------------------------------------------------------------------------------------
What are the requirements for submission of nonclinical laboratory studies?                        514.80(b)(4)(
                                                                                                    iii)(A)
----------------------------------------------------------------------------------------------------------------
What are the requirements for submission of clinical laboratory data?                              514.80(b)(4)(
                                                                                                    iii)(B)
----------------------------------------------------------------------------------------------------------------
When must results of clinical trials conducted by or for the applicant be reported?                514.80(b)(4)(
                                                                                                    iii)(C)
----------------------------------------------------------------------------------------------------------------
                                                                                                   514.80(b)(4)(
                                                                                                    iv) Adverse
                                                                                                    Drug
                                                                                                    Experiences
----------------------------------------------------------------------------------------------------------------
How do I report product/manufacturing defects and adverse drug experiences not previously          514.80(b)(4)(
 reported to FDA?                                                                                   iv)(A)
----------------------------------------------------------------------------------------------------------------
What are the requirements for submitting adverse drug experiences cited in literature?             514.80(b)(4)(
                                                                                                    iv)(B)
----------------------------------------------------------------------------------------------------------------
What are the requirements for submitting adverse drug experiences in postapproval studies and      514.80(b)(4)(
 clinical trials?                                                                                   iv)(C)
----------------------------------------------------------------------------------------------------------------
                                                                                                   514.80(b)(5)
                                                                                                    Other
                                                                                                    Reporting
----------------------------------------------------------------------------------------------------------------
Can FDA request that an applicant submit information at different times than stated specifically   514.80(b)(5)(
 in this regulation?                                                                                i) Special
                                                                                                    Drug
                                                                                                    Experience
                                                                                                    Report
----------------------------------------------------------------------------------------------------------------
What are the requirements for submission of advertisement and promotional labeling to FDA?         514.80(b)(5)(
                                                                                                    ii)
                                                                                                    Advertisemen
                                                                                                    ts and
                                                                                                    Promotional
                                                                                                    Material
----------------------------------------------------------------------------------------------------------------
What are the requirements for adding a new distributor to the approved application?                514.80(b)(5)(
                                                                                                    iii)
                                                                                                    Distributor'
                                                                                                    s Statement
----------------------------------------------------------------------------------------------------------------
What labels and how many labels need to be submitted for review?                                   514.80(b)(5)(
                                                                                                    iii)(A)
----------------------------------------------------------------------------------------------------------------
What changes are required and allowed to distributor labeling?                                     514.80(b)(5)(
                                                                                                    iii)(A)(I)
----------------------------------------------------------------------------------------------------------------
What are the requirements for making other changes to the distributor labeling?                    514.80(b)(5)(
                                                                                                    iii)(A)(II)
----------------------------------------------------------------------------------------------------------------
What information should be included in each new distributor's signed statement?                    514.80(b)(5)(
                                                                                                    iii)(B)(I)
                                                                                                    through
                                                                                                    (B)(V)
----------------------------------------------------------------------------------------------------------------

[[Page 5059]]

 
What are the conditions for submitting information that is common to more than one application?    514.80(c)
 (i.e., can I submit common information to one application?)                                        Multiple
                                                                                                    Applications
----------------------------------------------------------------------------------------------------------------
What information has to be submitted to the common application and related application?            514.80(c)(1)
                                                                                                    through
                                                                                                    (c)(4)
----------------------------------------------------------------------------------------------------------------
What forms do I need?                                                                              514.80(d)
What are Forms FDA 1932 and 2301?                                                                   Reporting
How can I get them?                                                                                 Forms
Can I use computer-generated equivalents?
----------------------------------------------------------------------------------------------------------------
How long must I maintain Form FDA 1932 and records and reports of other required information,      514.80(e)
 i.e., how long do I need to maintain this information?                                             Records to
                                                                                                    be
                                                                                                    Maintained
----------------------------------------------------------------------------------------------------------------
What are the requirements for allowing access to these records and reports, and copying by         514.80(f)
 authorized FDA officer or employee?                                                                Access to
                                                                                                    Records and
                                                                                                    Reports
----------------------------------------------------------------------------------------------------------------
How do I obtain Forms FDA 1932 and 2301?                                                           514.80(g)
Where do I mail FDA's required forms, records, and reports?                                         Mailing
                                                                                                    Address
----------------------------------------------------------------------------------------------------------------
What happens if the applicant fails to establish, maintain, or make the required reports?          514.80(h)
What happens if the applicant refuses to allow FDA access to, and/or copying and/or verify          Withdrawal
 records and reports?                                                                               of Approval
----------------------------------------------------------------------------------------------------------------
Does an adverse drug experience reflect a conclusion that the report or information constitutes    514.80(i)
 an admission that the drug caused an adverse effect?                                               Disclaimer
----------------------------------------------------------------------------------------------------------------

    (a) Applicability. (1) Each applicant and nonapplicant must 
establish and maintain indexed, separate, and complete files containing 
full records of all information pertinent to safety or effectiveness of 
a new animal drug that has not been previously submitted as part of the 
NADA or ANADA. Such records must include information from domestic, as 
well as foreign sources.
    (2) Each applicant must submit reports of data, studies, and other 
information concerning experience with new animal drugs to the Food and 
Drug Administration (FDA) for each approved NADA and ANADA, as required 
in this section. A nonapplicant must submit data, studies, and other 
information concerning experience with new animal drugs to the 
appropriate applicant, as required in this section. The applicant, in 
turn, must report the nonapplicant's data, studies, and other 
information to FDA. Applicants and nonapplicants must submit data, 
studies, and other information described in this section from domestic, 
as well as foreign sources.
    (3) FDA reviews the records and reports required in this section to 
facilitate a determination under section 512(e) of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 360b) as to whether there may be 
grounds for suspending or withdrawing approval of the NADA or ANADA.
    (4) The requirements of this section also apply to any approved 
Type A medicated article. In addition, the requirements contained in 
Sec. 514.80(b)(1), (b)(2), and (b)(4)(iv) apply to any approved Type A 
medicated article incorporated in animal feeds.
    (5) The records and reports referred to in this section are in 
addition to those required by the current good manufacturing practice 
regulations in parts 211, 225, and 226 of this chapter.
    (b) Reporting requirements--(1) Three-day NADA/ANADA field alert 
report. This report provides information pertaining to product and 
manufacturing defects that may result in serious adverse drug events. 
The applicant (or nonapplicant through the applicant) must submit the 
report to the appropriate FDA District Office or local FDA resident 
post within 3 working days of first becoming aware that a defect may 
exist. The information initially may be provided by telephone or other 
telecommunication means, with prompt written followup using Form FDA 
1932 ``Veterinary Adverse Drug Reaction, Lack of Effectiveness, Product 
Defect Report.'' The mailing cover for these reports must be plainly 
marked ``3-Day NADA/ANADA Field Alert Report.''
    (2) Fifteen-day NADA/ANADA alert report--(i) Initial report. This 
report provides information on each serious, unexpected adverse drug 
event, regardless of the source of the information. The applicant (or 
nonapplicant through the applicant) must submit the report to FDA 
within 15 working days of first receiving the information. The report 
must be submitted on Form FDA 1932, and its mailing cover must be 
plainly marked ``15-Day NADA/ANADA Alert Report.''
    (ii) Followup report. The applicant must promptly investigate all 
adverse drug events that are the subject of 15-day NADA/ANADA alert 
reports. If this investigation reveals significant new information, a 
followup report must be submitted within 15 working days of receiving 
such information. A followup report must be submitted on Form FDA 1932, 
and its mailing cover must be plainly marked ``15-Day NADA/ANADA Alert 
Report Followup.'' The followup report must state the date of the 
initial report and provide the additional information. If additional 
information is sought but not obtained within 3 months of the initial 
report, a followup report is required describing the steps taken and 
why additional information was not obtained.
    (iii) Summary report of increased frequency of adverse drug 
experience. The applicant must periodically review the incidence of 
reports of adverse drug experiences to determine if there has been an 
increased frequency of serious (expected and unexpected) adverse drug 
events. The applicant must report as soon as possible, but in any case 
within 15 working days of determining that there is an increased 
frequency of serious (expected and unexpected) adverse drug events. 
Summaries of reports of increased frequency of adverse drug events must 
be submitted in narrative form. The summaries must state the time 
period on which the increased frequency is based, time

[[Page 5060]]

period comparisons in determining increased frequency, references to 
any previously submitted Form FDA 1932, the method of analysis, and the 
interpretation of the results. The summaries must be submitted under 
separate cover and may not be included, except for reference purposes, 
in a periodic drug experience report. The applicant must evaluate the 
increased frequency of serious (expected or unexpected) adverse drug 
events at least as often as reporting of periodic drug experience 
reports.
    (3) Nonapplicant report. Nonapplicants must forward reports of 
adverse drug experiences to the applicant within 3 working days of 
first receiving the information. The applicant must then submit the 
report(s) to FDA as required in this section. The nonapplicant must 
maintain records of all nonapplicant reports, including the date the 
nonapplicant received the information concerning adverse drug 
experiences, the name and address of the applicant, and a copy of the 
adverse drug experience report including the date such report was 
submitted to the applicant. If the nonapplicant elects to also report 
directly to FDA, the nonapplicant should submit the report on Form FDA 
1932 within 15 working days of first receiving the information.
    (4) Periodic drug experience report. This report must be 
accompanied by a completed Form FDA 2301 ``Transmittal of Periodic 
Reports and Promotional Materials for New Animal Drugs.'' It must be 
submitted every 6 months for the first 2 years following approval of an 
NADA or ANADA and yearly thereafter. Reports required by this section 
must contain data and information for the full reporting period. The 6-
month periodic drug experience reports must be submitted within 30 days 
following the end of the 6-month reporting period. The yearly periodic 
drug experience reports must be submitted within 60 days of the 
anniversary date of the approval of the NADA or ANADA. Any previously 
submitted information contained in the report must be identified as 
such. For yearly (annual) periodic drug experience reports, the 
applicant may petition FDA to change the date of submission or 
frequency of reporting, and after approval of such petition, file such 
reports on the new filing date or at the new reporting frequency. Also, 
FDA may require a report at different times or more frequently. The 
periodic drug experience report must contain the following:
    (i) Distribution data. Information about the distribution of each 
new animal drug product, including information on any distributor-
labeled product. This information must include the total number of 
distributed units of each size, strength, or potency (e.g., 100,000 
bottles of 100 5-milligram tablets; 50,000 10-milliliter vials of 5 
percent solution). This information must be presented in two 
categories: quantities distributed domestically and quantities 
exported.
    (ii) Labeling. Applicant and distributor current package labeling, 
including package inserts (if any). For large-size package labeling or 
large shipping cartons, a representative copy must be submitted (e.g., 
a photocopy of pertinent areas of large feed bags). A summary of any 
changes in labeling made since the last report (listed by date of 
implementation) must be included with the labeling or if there have 
been no changes, a statement of such fact must be included with the 
labeling.
    (iii) Nonclinical laboratory studies and clinical data not 
previously reported.
    (A) Copies of in vitro studies (e.g., mutagenicity) and other 
nonclinical laboratory studies conducted by or otherwise obtained by 
the applicant.
    (B) Copies of published clinical trials of the new animal drug (or 
abstracts of them) including clinical trials on safety and 
effectiveness, clinical trials on new uses, and reports of clinical 
experience pertinent to safety conducted by or otherwise obtained by 
the applicant. Review articles, papers, and abstracts in which the drug 
is used as a research tool, promotional articles, press clippings, and 
papers that do not contain tabulations or summaries of original data 
are not required to be reported.
    (C) Descriptions of, or if available, prepublication manuscripts 
relating to completed clinical trials conducted by or otherwise known 
to the applicant. Supporting information is not to be reported. A study 
must be submitted no later than 1 year after completion of research.
    (iv) Adverse drug experiences. (A) Product/manufacturing defects 
and adverse drug experiences not previously reported under 
Sec. 514.80(b)(1) and (b)(2) must be reported individually on Form FDA 
1932.
    (B) Reports of adverse drug experiences in the literature must be 
noted in the periodic drug experience report. A bibliography of 
pertinent references must be included with the report. Upon FDA's 
request, the applicant must provide a full text copy of these 
publications.
    (C) Reports of previously not reported adverse drug experiences 
that occur in postapproval studies must be reported separately from 
other experiences in the periodic drug experience report and clearly 
marked or highlighted.
    (5) Other reporting--(i) Special drug experience report. Upon 
written request, FDA may require that the applicant submit a report 
required under Sec. 514.80 at different times or more frequently than 
the timeframes stated in Sec. 514.80.
    (ii) Advertisements and promotional labeling. The applicant must 
submit at the time of initial dissemination one set of specimens of 
mailing pieces and other labeling for prescription and over-the-counter 
new animal drugs. For prescription new animal drugs, the applicant must 
also submit one set of specimens of any advertisement at the time of 
initial publication or broadcast. Mailing pieces and labeling designed 
to contain product samples must be complete except that product samples 
may be omitted. Each submission of promotional material must be 
accompanied by a completed Form FDA 2301.
    (iii) Distributor's statement. At the time of initial distribution 
of a new animal drug product by a distributor, the applicant must 
submit a special drug experience report accompanied by a completed Form 
FDA 2301 containing the following:
    (A) The distributor's current product labeling.
    (1) The distributor's labeling must be identical to that in the 
approved NADA/ANADA except for a different and suitable proprietary 
name (if used) and the name and address of the distributor. The name 
and address of the distributor must be preceded by an appropriate 
qualifying phrase such as ``manufactured for'' or ``distributed by.''
    (2) Other labeling changes must be the subject of a supplemental 
NADA or ANADA as described under Sec. 514.8.
    (B) A signed statement by the distributor stating:
    (1) The category of the distributor's operations (e.g., wholesale 
or retail),
    (2) That the distributor will distribute the new animal drug only 
under the approved labeling,
    (3) That the distributor will advertise the product only for use 
under the conditions stated in the approved labeling,
    (4) That the distributor will adhere to the records and reports 
requirements of this section, and
    (5) That the distributor is regularly and lawfully engaged in the 
distribution or dispensing of prescription products if the product is a 
prescription new animal drug.
    (c) Multiple applications. Whenever an applicant is required to 
submit a periodic drug experience report under

[[Page 5061]]

the provisions of Sec. 514.80(b)(4) with respect to more than one 
approved NADA or ANADA for preparations containing the same new animal 
drug so that the same information is required to be reported for more 
than one application, the applicant may elect to submit as a part of 
the report for one such application (the primary application) all the 
information common to such applications in lieu of reporting separately 
and repetitively on each. If the applicant elects to do this, the 
applicant must do the following:
    (1) State when a report applies to multiple applications and 
identify all related applications for which the report is submitted by 
NADA or ANADA number.
    (2) Ensure that the primary application contains a list of the NADA 
or ANADA numbers of all related applications.
    (3) Submit a completed Form FDA 2301 to the primary application and 
each related application with reference to the primary application by 
NADA/ANADA number and submission date for the complete report of the 
common information.
    (4) All other information specific to a particular NADA/ANADA must 
be included in the report for that particular NADA/ANADA.
    (d) Reporting forms. Applicant must report adverse drug experiences 
and product/manufacturing defects on Form FDA 1932, ``Veterinary 
Adverse Drug Reaction, Lack of Effectiveness, Product Defect Report.'' 
Periodic drug experience reports and special drug experience reports 
must be accompanied by a completed Form FDA 2301 ``Transmittal of 
Periodic Reports and Promotional Material for New Animal Drugs,'' in 
accordance with directions provided on the forms. Computer-generated 
equivalents of Form FDA 1932 or Form FDA 2301, approved by FDA prior to 
use, may be used. Form FDA 1932 and Form FDA 2301 may be obtained on 
the Internet at http://www.cvm.fda.gov/cvm, by telephoning the Division 
of Surveillance (HFV-210), or by submitting a written request to the 
following address: Food and Drug Administration, Center for Veterinary 
Medicine, Division of Surveillance (HFV-210), 7500 Standish Pl., 
Rockville, MD 20855-2764.
    (e) Records to be maintained. The applicants and nonapplicants must 
maintain records and reports of all information required by this 
section for a period of 5 years after the date of submission.
    (f) Access to records and reports. The applicant and nonapplicant 
must, upon request from any authorized FDA officer or employee, at all 
reasonable times, permit such officer or employee to have access to 
copy and to verify all such required records and reports.
    (g) Mailing addresses. Completed 15-day alert reports, periodic 
drug experience reports, and special drug experience reports must be 
submitted to the following address: Food and Drug Administration, 
Center for Veterinary Medicine, Document Control Unit (HFV-199), 7500 
Standish Pl., Rockville, MD 20855-2764. Three-day alert reports must be 
submitted to the appropriate FDA district office or local FDA resident 
post. Addresses for district offices and resident posts may be obtained 
from the Internet at http://www.fda.gov.
    (h) Withdrawal of approval. If FDA finds that the applicant has 
failed to establish the required records, or has failed to maintain 
those records, or failed to make the required reports, or has refused 
access to an authorized FDA officer or employee to copy or to verify 
such records or reports, FDA may withdraw approval of the application 
to which such records or reports relate. If FDA determines that 
withdrawal of the approval is necessary, the agency shall give the 
applicant notice and opportunity for hearing, as provided in 
Sec. 514.200, on the question of whether to withdraw approval of the 
application.
    (i) Disclaimer. Any report or information submitted under this 
section and any release of that report or information by FDA will be 
without prejudice and does not necessarily reflect a conclusion that 
the report or information constitutes an admission that the drug caused 
or contributed to an adverse event. A person need not admit, and may 
deny, that the report or information constitutes an admission that a 
drug caused or contributed to an adverse event.

    Dated: January 21, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-2549 Filed 2-1-02; 8:45 am]
BILLING CODE 4160-01-S