[Federal Register: February 4, 2002 (Volume 67, Number 23)]
[Rules and Regulations]
[Page 5046-5061]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr04fe02-5]
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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
wkeller@cvm.fda.gov.
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
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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