[Federal Register Volume 68, Number 61 (Monday, March 31, 2003)]
[Rules and Regulations]
[Pages 15355-15369]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-7475]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 211, 226, 510, and 514

[Docket No. 88N-0038]
RIN 0910-AC42


Records and Reports Concerning Experience With Approved New 
Animal Drugs

AGENCY: Food and Drug Administration, HHS.

ACTION: Withdrawal of interim final rule and issuance of final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is withdrawing the 
interim final rule that it published on February 4, 2002. The interim 
final rule amended the regulations for records and reports concerning 
experiences with approved new animal drugs. FDA invited interested 
parties to comment on the interim final rule. As a result of those 
comments, this final rule more clearly defines the kinds of information 
to be maintained and submitted by new animal drug applicants for new 
animal drug applications (NADAs) or abbreviated new animal drug 
applications (ANADAs). In addition, the final rule revises the timing 
and content of certain reports to enhance their usefulness. This 
regulation will provide for protection of public and animal health and 
reduce unnecessary recordkeeping and reporting requirements.

DATES: This rule is effective June 30, 2003. The interim final rule 
published on February 4, 2002 (67 FR 5046), is withdrawn as of March 
31, 2003.

FOR FURTHER INFORMATION CONTACT: Glenn Peterson, Center for Veterinary 
Medicine (HFV-212), Food and Drug Administration, 7500 Standish Pl., 
Rockville, MD 20855, 301-827-0224, or [email protected]. Form FDA 
1932 and Form FDA 2301 may be obtained by calling the Food and Drug 
Administration, Center for Veterinary Medicine, Division of 
Surveillance at 301-827-6642.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of December 17, 1991 (56 FR 65581), FDA 
published

[[Page 15356]]

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 (FDA) 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 adopted the rule in modified form in 
an interim final rule. The scope and coverage of the interim final rule 
differed 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 covered only NADAs and ANADAs. The Animal Drug 
Availability Act of 1996 (ADAA) (21 U.S.C. 360b(a) and (m)) amended the 
statutory provisions in the act regarding medicated feeds and 
eliminated MFAs. Therefore, the interim final rule did not address 
MFAs. However, the interim final rule retained reporting requirements 
for adverse drug experiences (ADEs) 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 maintained a similar style 
and format, but removed many of the proposed records and reports 
requirements that are not necessary to monitor animal drugs.
    In response to initial concerns over duplicate reporting, FDA had 
removed proposed Sec.  514.82 from the interim final rule, which 
concerned records and reports from manufacturers, packers, labelers, 
and distributors other than the applicant. However, the agency did 
retain certain record and report requirements for nonapplicants 
(defined in new Sec.  514.3) (21 CFR 514.3)) and in Sec.  514.80(b) of 
the interim final rule. Under Sec.  514.80(b)(3), nonapplicants must 
submit reports of adverse events to applicants and, if they choose, 
also to FDA. FDA requires such reports under the authority of sections 
501 and 701 of the act (21 U.S.C. 351 and 371) and section 512(l) of 
the act. Keeping track of such reports helps the agency assure that the 
new animal drug meets the requirements of the act as to safety as 
required by section 501. Additionally, section 512(l) requires 
applicants to report adverse events that the applicant has ``received 
or otherwise obtained.'' In this instance, FDA is requiring that the 
applicant ``receive'' reports from other parties that are listed on the 
label by requiring that the nonapplicants give the reports to the 
applicants. For purposes of clarity, the agency also made some changes 
to the text and organization of the interim final rule.
    On February 4, 2002, the interim final rule on ADE records and 
reports was published in the Federal Register with an effective date of 
August 5, 2002 (67 FR 5046). In the Federal Register of July 31, 2002 
(67 FR 49568), the effective date of the interim final rule published 
at 67 FR 5046 was delayed indefinitely. We received and reviewed 33 
comments on the interim final rule from 4 commenters. In response to 
those comments, the agency is withdrawing the interim final rule 
published February 4, 2002 (67 FR 5046) and issuing this final rule.

II. Comments on the Interim Final Rule

    The agency received four sets of comments on the interim final rule 
for records and reports, three from industry associations, and one from 
a pharmaceutical company. A discussion of the comments and our response 
follows. In the interest of clarity, the comments are addressed by 
relevant section of the rule, with general comments following.

A. Definition of Adverse Drug Experience (Sec.  514.3)

    (Comment 1) One comment suggested that the definition of ``Adverse 
Drug Experience'' be changed from ``Failure of a new animal drug to 
produce its expected pharmacological or clinical effect (lack of 
effectiveness)'' to ``Unusual failure of a new animal drug to produce 
its expected pharmacological or clinical effect (lack of 
effectiveness).'' The comment states that it is the unusual failure to 
respond to therapy that is of concern. The agency stated in comment 7 
of the preamble to the interim final rule that failures to respond to 
therapy were expected. The comment responded ``that current product 
labeling does not usually address efficacy failures.'' According to the 
comment, a failure not listed on the label would be considered 
unexpected and thus must be a 15-day NADA/ANADA alert report.
    FDA agrees with the comment and does not intend for all 
effectiveness failures to be defined as ADEs. To this end, FDA will 
clarify the definition by changing the phrase ``expected 
pharmacological or clinical effect (lack of effectiveness)'' to 
``expected pharmacological or clinical effect (lack of expected 
effectiveness).'' FDA also will continue to work with applicants and 
provide advice to applicants in determining reportable events. For 
example, consider a drug that is expected to cure 80 percent of the 
animals treated, but cures 90 percent. While there is still a 10 
percent failure rate, the success rate is above the expected rate of 80 
percent; therefore, this is not a reportable ADE. However, if a drug is 
expected to cure 80 percent of the animals treated, but cures only 40 
percent, which is a 60 percent failure rate and below the expected 
rate, a reportable ADE has occurred. This would be reported as a 15-day 
NADA/ANADA alert report since it is an unexpected ADE.

B. Definition of Applicant (Sec.  514.3)

    (Comment 2) One comment suggested that the definition of 
``Applicant'' be changed from ``Applicant is a person who owns a new 
animal drug application or ANADA'' to ``Applicant is a person who holds 
a new animal drug application or an ANADA.'' The comment explained that 
the actual owner of an application may be different from the sponsor of 
the application. It may be a parent company with the U.S. company being 
the sponsor. The comment agreed with the agency's statement in the 
preamble to the interim final rule that the term ``applicant is limited 
to the holder of an approved application (NADA or ANADA) * * *.''
    The agency will revise the definition of ``applicant'' in Sec.  
514.3 as follows:
    ``Applicant is a person or entity who owns or holds on behalf of 
the owner the approval for an NADA or an ANADA, and is responsible for 
compliance with applicable provisions of the act and regulations.''

[[Page 15357]]

C. Definition of Increased Frequency of Adverse Drug Experience and 
Summary Report of Increased Frequency of Adverse Drug Experience 
(Sec. Sec.  514.3 and 514.80(b)(2)(iii))

    (Comment 3) One comment requested that FDA provide additional 
clarification of this requirement or delete the requirement of a 
summary report. The comment acknowledged and appreciated FDA's 
willingness to make changes in response to previous comments. However, 
it stated that there are doubts that this requirement can be met ``even 
with the adjustment for drug exposure.'' The comment stated that the 
adjustment for drug exposure based on distribution data would be 
unreliable given that distribution data does not ``equate[d] with the 
amount actually used (exposure) in any given time period.'' Also, the 
comment maintained that this requirement of a summary report is 
``troubling'' because it is required to be submitted within 15 working 
days.
    In retrospect, FDA does concur with the concern about requiring 
summary reports within 15 working days. FDA has modified Sec.  
514.80(b)(2)(iii) to require that information be reported in the 6-
month and yearly periodic drug experience reports under Sec.  
514.80(b)(4)(v). FDA also has made a conforming change to Sec.  
514.80(a)(4) to include Sec.  514.80(b)(4)(v).
    The following is the change to former Sec.  514.80(b)(2)(iii), now 
under Sec.  514.80(b)(4)(v):

    (v) 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 evaluate the increased frequency of 
serious (expected or unexpected) adverse drug events at least as 
often as reporting of periodic drug experience reports. The 
applicant must report the increased frequency of serious (expected 
and unexpected) adverse drug events in the periodic drug experience 
report. 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 
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 
in a separate section within the periodic drug experience report.

    The following is the change to Sec.  514.80(a)(4):
    ``(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), (b)(4)(iv), and (b)(4)(v) apply to any 
approved Type A medicated article incorporated in animal feeds.''

D. Definition of Serious Adverse Drug Experience (Sec.  514.3)

    (Comment 4) One comment asked FDA to change the definition of a 
``Serious adverse drug experience'' from ``an adverse event that is 
fatal or life threatening, requires professional intervention.'' to 
``an adverse event that is fatal or is a life-threatening event that 
requires professional intervention.'' The comment stated that the 
listing of events ``adds confusion as to whether all or just one of the 
conditions need to be present for the event to meet the definition of 
serious.'' The comment questioned whether ``professional intervention'' 
is necessary for every listed condition in the definition for the event 
to be considered a serious ADE. Another comment asked that ``requires 
professional intervention'' be removed from the list since some events 
involving veterinary intervention are not serious.
    In order to clarify the issue, FDA has added ``or'' between each 
term so that it is clear that each event listed is independent of any 
other event. Any one of the events listed will be considered a serious 
ADE. Both comments suggest that the ADE be considered serious only in 
the case where the fatal or life-threatening event requires 
professional intervention. FDA believes that a fatal or life-
threatening event is serious regardless of whether professional 
intervention is sought for treatment. Thus, FDA will not change the 
definition to require professional intervention for each event. Events 
that are life threatening or that require professional intervention 
will be considered serious ADEs. FDA believes that any professional 
veterinary intervention is serious enough in nature to require 
reporting.
    (Comment 5) One comment requested clarification of the portion of 
the definition that ``requires professional intervention'' as to 
whether this means that any reports from veterinarians to the applicant 
are considered serious.
    FDA addressed this issue in comment 10 of the preamble in the 
interim final rule and added professional intervention to clarify the 
definition of seriousness for animal drugs. We believe that the 
definition is appropriate.
    (Comment 6) One comment questioned whether ``infertility'' is a 
serious ADE. The comment stated that infertility following 
administration is rarely drug-related, and that many types of 
infertility would not be serious.
    We disagree with the comment. Purebred producers (e.g., of cats, 
dogs, or cattle) would not want to use a product that may impair 
fertility unless necessary. Therefore, FDA believes that it is 
important to make label changes regarding fertility as quickly as 
possible, thus providing important labeling information for the end 
user. FDA will not remove ``infertility'' from the definition.
    (Comment 7) One comment stated that the ``unique aspects of 
evaluating animals that are housed and managed as a group'' should be 
included in the definition. The comment proposed that FDA use the 
International Cooperation on Harmonization of Technical Requirements 
for Registration of Veterinary Medicinal Products (VICH) definition of 
serious ADE. The comment used an example situation in which the 
background frequency of death in animals not treated is higher than 
animals treated with the drug. FDA addressed a similar issue in the 
preamble of the interim final rule under comment 7. The VICH guidance 
documents are in early development, and once completed it is the 
intention of FDA to adopt and implement them in a manner consistent 
with its existing regulations. At this time, it is premature to adopt 
VICH definitions.
    (Comment 8) One comment stated that a patient examination should 
not be considered professional intervention if there is no 
administration or dispensing of medications. According to the comment, 
this should not be the sole means of classifying an event as serious. 
The comment further stated that if there is an examination and no 
treatment is indicated by the veterinarian, then ``professional 
intervention in the outcome of the case has not occurred.''
    An examination with no medical or surgical intervention/treatment 
or any treatment is a reportable ADE. If professional services of a 
veterinarian are engaged then this is considered an intervention 
incident. For example, if an over-the-counter (OTC) or prescription 
(Rx) drug product is given to the animal prior to veterinary 
intervention and an adverse drug reaction occurs, then the 
veterinarian, upon examination, may have important information 
concerning the event. As explained in the preamble of the interim final 
rule, FDA added the words ``professional intervention'' to clarify the 
definition of seriousness for animal drugs. FDA believes that the 
definition is appropriate.
    The following is the change to the definition for ``serious adverse 
drug experience'' in Sec.  514.3:

[[Page 15358]]

    ``Serious adverse drug experience is an adverse event that is 
fatal, or life-threatening, or requires professional intervention, or 
causes an abortion, or stillbirth, or infertility, or congenital 
anomaly, or prolonged or permanent disability, or disfigurement.''

E. Definition of Unexpected Adverse Drug Experience (Sec.  514.3)

    (Comment 9) One comment suggested that FDA change the definition of 
``Unexpected drug experience'' from ``an adverse event that is not 
listed in the current labeling for the new animal drug.'' to ``an 
adverse event that is not listed in the current labeling for the new 
animal drug or reported in its Freedom of Information Summary(ies).'' 
The comment highlighted the inclusion of the NADA file in the current 
rule's definition of ``unexpected drug experience'' and that those 
incidences referenced in the NADA file may not be captured on the 
label. Therefore, there is concern that this change from the current 
Sec.  510.300(b)(2)(i) will increase the number of reports to the NADA 
file. There is also a concern that this would increase FDA's workload 
for labeling changes, especially for Type A medicated articles and OTC 
products. The comment maintained that it is inappropriate for FDA to 
exclude the NADA file, and include only the current label, from the 
definition since the freedom of information summary of the NADA file is 
publicly available. The comment further stated that it is inappropriate 
since the applicant is the primary source of the ADE and is responsible 
for determining if the report is unexpected.
    We disagree with the comment. Although the freedom of information 
summary is a publicly available document, it is neither a practical 
substitute for a label, nor is it widely distributed and available with 
the label.
    (Comment 10) One comment posed a scenario where an ADE is commonly 
recognized and not on the current label. It suggested that since the 
ADE is commonly recognized, it should be expected by FDA. The comment 
asked for the agency's expectation/position on this scenario.
    FDA requires that recognized ADEs be on the label. It is the 
position of the Center for Veterinary Medicine (CVM) that any serious, 
unexpected ADE be reported under Sec.  514.80(b)(2).

F. Applicability of Records and Reports Concerning Experience With 
Approved New Animal Drugs (Sec.  514.80(a)(1))

    (Comment 11) One comment objected to the requirement of 
``separate'' filing systems in the sentence ``Each applicant and 
nonapplicant must establish and maintain indexed, separate, and * * *'' 
The comment stated that this is a new requirement not present in the 
proposed rule for records and reports and it is not in Sec.  
514.300(a). Further, the comment argued that it is the applicant's 
decision to determine whether files are stored separately or as part of 
another filing system. The comment requested an explanation for this 
change, and proposed that the word ``separate'' be deleted.
    It was not FDA's intention to make the determination as to whether 
files are stored separately or as part of another filing system. During 
FDA's review of comments on the proposed rule for records and reports 
concerning duplicate reporting, it was determined that the proposed 
Sec.  514.82 (nonapplicant) information should be combined with 
proposed Sec.  514.80 (applicant) information. The use of the word 
``separate'' in this sentence was FDA's attempt to combine the 
information from proposed Sec.  514.82 with Sec.  514.80. 
Unfortunately, the combined verbiage has lead to this unintended 
reading by the commenter. Also, it was not FDA's intention that 
nonapplicants ``establish and maintain indexed, separate, and complete 
files containing full records of all information * * * of a new animal 
drug * * *'' It is the intention of FDA that nonapplicants ``establish 
and maintain indexed, separate, and * * *'' of only the information 
that they receive or otherwise obtain. Therefore, FDA has separated 
requirements for applicants from requirements for nonapplicants in 
order to clarify the meaning.
    (Comment 12) One comment proposed that the clause ``* * * that has 
not been previously submitted as part of the NADA or ANADA'' be changed 
to ``* * * that has not been previously submitted as part of an 
investigational new animal drug (INAD) file, the NADA or ANADA.'' The 
comment expressed concern that the studies/information submitted to the 
INAD would be excluded from the exemption of being ``previously 
submitted'' until the sponsor incorporated the information by reference 
into the NADA/ANADA file.
    FDA believes that changing the regulation to include INADs is 
outside the scope of this regulation. The scope of records and reports 
is for experiences with approved new animal drugs, not investigational 
uses. The consequences of adding INADs to this regulation would be that 
applicants of INADs would have to submit the information and data under 
Sec.  514.80. Therefore, FDA will not change the regulation to include 
INADs.
    The following is the change to (Sec.  514.80(a)(1)):

    (a) Applicability. (1) Each applicant must establish and 
maintain indexed 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.
    Each nonapplicant must establish and maintain indexed and 
complete files containing full records of all information pertinent 
to safety or effectiveness of a new animal drug that is received or 
otherwise obtained by the nonapplicant. Such records must include 
information from domestic as well as foreign sources.

G. Three-Day NADA/ANADA Field Alert Report (Sec.  514.80(b)(1))

    (Comment 13) One comment asked what district office should be 
notified for 3-day NADA/ANADA field alert reports for U.S.-approved 
products that are manufactured outside of the United States.
    Applicants should contact their FDA district office to determine 
the procedure for reporting 3-day alerts.

H. Fifteen-Day NADA/ANADA Alert Report (Sec.  514.80(b)(2))

    (Comment 14) One comment opposed the use of the terminology 
``regardless of source of the information'' in the reporting 
requirement for 15-day NADA/ANADA alert reports. The comment stated 
that ``regardless of source'' is overly broad. According to the 
comment, an ADE found by an employee of the company while browsing a 
chat room on the Internet would have to be reported to FDA. The comment 
also expressed concern that serious adverse events outside the United 
States be reported to FDA within 15 days.
    The phrase ``regardless of source'' was added to emphasize that the 
agency wanted all reports of ADEs. A legitimate source is an 
identifiable reporter, an identifiable product, and one or more ADEs in 
animals or humans, regardless of whether the source is the Internet. If 
the event is a serious, unexpected adverse drug event then it must be 
reported in a 15-day NADA/ANADA alert report. All domestic and foreign 
ADEs for the U.S.-approved application should be submitted under Sec.  
514.80(b)(2) or (b)(4)(iv).
    (Comment 15) One comment requested that FDA elaborate on the 
requirement of submission of reports of ADEs from foreign sources as it 
relates to Sec.  514.80(a)(2). The comment stated that this requirement 
is not consistent

[[Page 15359]]

with Sec.  510.300 and will increase the number of reports.
    The burden for reporting domestic and foreign ADEs is the same 
under Sec.  510.300. Foreign ADEs are required to be reported under the 
current regulations, although this requirement is not stated as 
explicitly in the current regulation as under Sec.  514.80(a)(2). FDA 
is adding the language concerning foreign sources in order to make the 
rule more clear.
    (Comment 16) One comment requested that applicants should not have 
to report cases where the reporter believes that an event is not drug 
related and the reporter does not want the case to be filed with FDA.
    The ADE must be reported regardless of whether or not the reporter 
considers it to be drug related, if it meets the definition of an ADE 
(see 21 CFR 514.3), or whether a caller wishes it not to be reported. 
FDA will provide assistance on a case-by-case basis for specific 
incidences that the applicant or other reporter still believes should 
be excluded.

I. Nonapplicant Report (Sec.  514.80(b)(3))

    (Comment 17) One comment recommended that in order to avoid 
confusion and over-reporting, all ADE reports should be submitted to 
CVM by the applicant, and that the sentence ``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'' should be deleted from the regulation. The comment 
maintained that if the nonapplicant reports to FDA in the 15-day period 
and it is determined by the applicant that it is not a serious, 
unexpected event, FDA might come to the conclusion that the applicant 
is under-reporting.
    FDA does not concur with this recommendation. FDA believes that it 
is important for the nonapplicant to have a mechanism to report 
voluntarily. FDA will evaluate any nonapplicant report it receives to 
determine whether the report is of a serious, unexpected ADE.

J. Periodic Drug Experience Report--Distribution Data (Sec.  
514.80(b)(4)(i))

    (Comment 18) One comment questioned the need to report distribution 
data on the amounts of product exported outside the United States, and 
if the data are to be reported, how they will be used. The comment 
stated that since foreign ADEs are not required to be reported, there 
is no benefit for reporting amounts exported.
    Foreign reports have to be submitted under Sec.  514.80. Foreign 
ADEs for the U.S.-approved application must be submitted under Sec.  
514.80(b)(2) or (b)(4)(iv). These data will be used in a similar manner 
as domestic distribution data in determining if an increased frequency 
of ADE exists.

K. Periodic Drug Experience Report--Nonclinical Laboratory Studies and 
Clinical Data Not Previously Reported (Sec.  514.80(b)(4)(iii))

    (Comment 19) One comment maintained that studies conducted to 
support a future claim should not be reported in the periodic drug 
experience report. The comment suggested that because sponsors make 
submissions to CVM's Office of New Animal Drug Evaluation (ONADE) for 
its review, and also report to CVM's Office of Surveillance and 
Compliance, the confusion could be eliminated by changing the title of 
this section from ``Nonclinical laboratory studies and clinical data 
not previously reported'' to ``Nonclinical laboratory studies and 
clinical data not previously submitted.''
    FDA believes that such a change is not necessary. This requirement 
only pertains to data not previously reported to CVM, including 
submissions to ONADE and reports to the Office of Surveillance and 
Compliance.

L. Periodic Drug Experience Report--Nonclinical Laboratory Studies and 
Clinical Data Not Previously Reported--Prepublication Manuscripts 
(Sec.  514.80(b)(4)(iii)(C))

    (Comment 20) One comment questioned the value and need to submit 
prepublication manuscripts and strongly recommended deletion of this 
requirement. The comment stated that such manuscripts are no better 
than draft reports and submission of these to entities other than the 
publisher may be prohibited by a journal in its publication policy. 
Additionally, it stated that the applicant could comply with the 
requirements for submission of a study within 1 year of its completion 
only when the study is conducted by or for the applicant.
    FDA concurs with the recommendation and has revised this section of 
the regulation.
    The following is the change to Sec.  514.80(b)(4)(iii)(C):
    (C) Descriptions of completed clinical trials conducted by or for 
the applicant must be submitted no later than 1 year after completion 
of research. Supporting information is not to be reported.

M. Periodic Drug Experience Report--Adverse Drug Experiences (Sec.  
514.80(b)(4)(iv))

    (Comment 21) One comment stated that FDA limited the scope of a 
manufacturing/product defect by changing the definition in Sec.  
514.80(g) in response to comment 12 of the interim final rule. The 
comment stated, ``the scope of what is considered to be a 
manufacturing/product defect has now been limited to that which is a 
problem associated with public health or animal safety or that is a 
significant, chemical, physical, or other change or deterioration in 
the drug product or significant defective packaging or labeling 
error.'' According to the comment, nonsignificant defects, which 
involve the physical appearance but have no impact on animal safety or 
public health, do not need to be reported since these defects are not 
included in the definition of manufacturing/product defects. The 
comment provided a specific example of a blister unit with a misaligned 
die-cut of a blister, which does not affect the integrity of the 
package seal or labeling or an empty blister well.
    Manufacturing/product defects are defined in Sec.  514.3. If a 
problem with the product does not fall under the definition in Sec.  
514.3, then it is not considered a manufacturing/product defect. The 
example of a misaligned die-cut of a blister unit may or may not be 
considered a manufacturer/product defect depending on whether it is or 
is not a deviation of a distributed product from the standard specified 
in the approved application or any other portion of the definition. 
Manufacturing/product defects that may result in a serious adverse drug 
event must be submitted as a 3-day NADA/ANADA field alert report. The 
requirement of a serious adverse drug event limits the number of 3-day 
reports. Nonserious manufacturing/product defects should be submitted 
in the periodic drug experience report. The manufacturing/product 
defects definition given in Sec.  514.3 does not pertain to the good 
manufacturing practice (GMP) regulations or other regulations outside 
of Sec.  514.80.

N. Periodic Drug Experience Report--Adverse Drug Experiences Not 
Previously Reported (Sec.  514.80(b)(4)(iv)(A))

    (Comment 22) One comment suggested that product/manufacturing 
defects, other than serious ones, should not have to be reported. FDA 
stated in the preamble of the interim final rule that FDA would limit 
its scope to

[[Page 15360]]

problems associated with public health or animal safety. According to 
the comment, the requirement of reporting product/manufacturing 
defects, other than serious ones, is not consistent with FDA's 
statement. The comment requested that 21 CFR 514.80(b)(4)(iv)(A) refer 
only to ADEs.
    FDA declines to make the proposed change because eliminating the 
provision as requested would leave a significant gap in the safety and 
effectiveness profile of a drug product. The agency would no longer 
receive information for product and manufacturing defects that may 
result in ``nonserious'' but significant unexpected adverse drug 
events, i.e., events not listed on the label of a particular drug 
product. These could include new symptoms and pathophysiologically-
related events such as increases in enzymes or blood counts that appear 
not to be serious by definition, but could negatively impact the effect 
of the drug product. Further, the applicant would not have to report 
product and manufacturing defects that may result in a lack of expected 
effectiveness.

O. Periodic Drug Experience Report--Adverse Drug Experiences in the 
Literature (Sec.  514.80(b)(4)(iv)(B))

    (Comment 23) One comment stated that applicants routinely have not 
submitted ADEs separate from the literature. According to the comment, 
applicants have limited ability to investigate incidents such as 
studies conducted by unrelated third parties. The comment requested 
that this section be deleted or reworded to clarify FDA's intent.
    FDA is not requesting that each individual ADE in the literature be 
submitted on Form FDA 1932. The use of Form FDA 1932 does not apply to 
Sec.  514.80(b)(4)(iv)(B). As the rule states, FDA is asking that ``a 
bibliography of pertinent references'' of the literature containing 
ADEs be submitted. A bibliographic listing from Medline or other 
database searches would be acceptable.

P. Periodic Drug Experience Report--Adverse Drug Experiences Occurring 
in Postapproval Studies That Are Not Previously Reported (Sec.  
514.80(b)(4)(iv)(C))

    (Comment 24) One comment noted that reporting ADEs from 
postapproval studies is duplicate reporting given that the study report 
is submitted to ONADE. The comment contended that this would be a 
considerable additional workload, especially for the first 2 years 
postapproval. Also, if this reporting requirement is not changed, the 
comment asked if FDA wanted these reports on Form FDA 1932. FDA 
disagrees that this would be additional work. This requirement only 
pertains to ADEs not previously reported to CVM. Any study reports 
previously submitted to ONADE do not have to be submitted again. 
Applicants are not required to submit these experiences on Form FDA 
1932.

Q. Other Reporting--Advertisements and Promotional Labeling (Sec.  
514.80(b)(5)(ii))

    (Comment 25) One comment stated that the regulation is not clear 
about the submission requirements for OTC and Rx promotional labeling. 
Further, the comment requested that the promotional labeling 
requirement be applicable to Rx products only, in accordance with 
current regulations.
    FDA believes that the regulation is clear about the submission 
requirement for OTC and Rx labeling. FDA declines to change the 
applicability to Rx products only. This is not a new proposal; it was 
included in the proposed rule for records and reports.

R. Other Reporting--Distributor's Statement--Current Product Labeling 
(Sec.  514.80(b)(5)(iii)(A)(1))

    (Comment 26) One comment suggested that, with regard to 
distributor's labeling, the qualifying phrase should not be limited to 
``manufactured for'' or ``distributed by.'' The comment argued that 
Sec.  201.1(h)(5) (21 CFR 201.1(h)(5)) provides the appropriate 
alternatives, which should also be permitted, and recommended that the 
last sentence in this section be changed.
    The agency concurs with the proposed revision and has revised this 
section.
    The following is the change to Sec.  514.80(b)(5)(iii)(A)(1):
    (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 as permitted by the regulations such as 
``manufactured for'' or ``distributed by.''

S. Other Reporting--Distributor's Signed Statements (Sec.  
514.80(b)(5)(iii)(B)(2) and (b)(5)(iii)(B)(3))

    (Comment 27) One comment noted that the current regulation Sec.  
514.8(a)(6)(iii) (21 CFR 514.8(a)(6)(iii)) requires the distributor to 
state that he/she will distribute the drug only under its approved 
labeling and that any other labeling or advertising will prescribe, 
recommend, or suggest use only under the approved labeling. According 
to the comment, Sec.  514.80(b)(5)(iii)(B)(2) and (b)(5)(iii)(B)(3) of 
the interim final rule omits the limitation on promotional labeling. 
The comment suggested that the language of 21 CFR 514.8(a)(6)(iii) be 
changed so that paragraph (b)(5)(iii)(B)(3) would read as follows: 
``(3) that the distributor will distribute the product only for use 
under the conditions stated in the approved labeling, and any other 
labeling or advertising will prescribe, recommend, or suggest its use 
only under the approved labeling.''
    The agency believes that the provisions of paragraph 
(b)(5)(iii)(B)(3) of the proposed rules are similar to those of Sec.  
514.8(a)(6)(iii), but have been simplified and written in plain 
language. However, to make the meaning clear, the agency has revised 
the section by replacing the word ``advertise'' with ``promote.''
    The following is the change to Sec.  514.80(b)(5)(iii)(B)(3):
    ``(3) That the distributor will promote the product only for use 
under the conditions stated in the approved labeling;''

T. Multiple Applications--Information Specific to a Particular NADA/
ANADA (Sec.  514.80(c)(4))

    (Comment 28) One comment stated that the requirements under 
``Multiple Applications'' do not appear to decrease, but may increase 
the burden on the applicant. In particular, the comment questioned the 
requirement under Sec.  514.80(c)(4) and requested clarification. The 
comment also expressed concern with the increased reporting burden due 
to the increasing number of approved combinations of drugs for use in 
feeds since the implementation of the ADAA. Further complicating the 
reporting issue is that frequently there are nonapplicants involved in 
the marketing of these combinations. The comment stated that, with the 
exception of ``promotional literature,'' there is rarely any other 
information to be reported. The comment suggested that the 
``promotional literature'' be submitted to the application held by 
either party--i.e., the nonapplicants or applicant--and not the 
application approved for the use of the combination of drugs.
    The provision of the regulation in question is currently codified 
under Sec.  510.300(b)(4)(ii). The current regulation and the proposal 
in the interim final rule are similar. There is no increase of the 
reporting burden. It is not the intention of FDA for the

[[Page 15361]]

implementation of Sec.  514.80(c) to be different from the current 
requirement under Sec.  510.300(b)(4)(ii). Only information specific to 
a particular NADA/ANADA that is not common to all the applications must 
be included in the report for that particular NADA/ANADA, for example, 
labeling. With regard to the comment that there is an increased 
reporting burden due to the ADAA, increased reporting is due to the 
increased number of approved applications, and not due to different 
requirements. FDA consequently believes that this is a reasonable 
reporting requirement.

U. Records to Be Maintained and Access to Records and Reports (Sec.  
514.80(e) and (f))

    (Comment 29) One comment asked where the primary repository for 
foreign report records (United States versus the foreign country) would 
reside.
    Sponsors should keep records wherever it is their customary 
business practice to keep them as long as the records are available to 
FDA for inspection.

V. General Comments on the Regulation

    (Comment 30) One comment requested that CVM adopt procedures for 
waiving the reporting of ADEs for NADAs/ANADAs. The comment suggested 
adopting procedures similar to FDA's Center for Drug Evaluation and 
Research's March 2001 draft publication entitled ``Guidance for 
Industry on Postmarketing Safety Reporting for Human Drug and 
Biological Products Including Vaccines.'' This guidance states that 
applicants under certain conditions may request waivers from submission 
of full ADE reports that are both nonserious and labeled.
    We disagree with the comment. The procedures in the draft guidance 
cited by the commenter only waive reporting such adverse experiences on 
FDA Form 3500A. The applicant still must collect and report these 
adverse experiences by providing a summary tabulation by body system 
and a narrative discussion about all adverse experiences in the 
periodic report. FDA also may request that the applicant submit these 
reports on the human form (FDA Form 3500A) within 5 calendar days after 
receipt of the agency's request. The final records and reports rule 
does not include such a summary tabulation or narrative discussion 
requirement. We believe that adding such a requirement would impose a 
greater burden on the regulated industry than the requirement of 
reporting such adverse events on Form FDA 1932 in periodic reports. 
Further, we believe it is crucial that all adverse drug experience 
information be submitted in a consistent manner and format to 
facilitate the agency's analysis of the information. For these reasons, 
we have not adopted the change proposed by this comment.
    (Comment 31) One comment asked if ADEs and product defects for 
unapproved products, which meet the requirements of 21 CFR part 
801(e)(1) of the act, should be reported.
    No, this regulation only pertains to approved new animal drugs.
    (Comment 32) One comment asked if a validated electronic signature 
in compliance with part 11 (21 CFR part 11) would suffice for an 
authorized signature on Form FDA 1932.
    Yes, an electronic signature that is compliant with part 11 will be 
acceptable.
    (Comment 33) One comment apparently has misinterpreted the table 
that outlines the purpose of each paragraph. In particular, the comment 
indicated belief that the purpose given for Sec.  514.80(b)(1) also 
pertained to the next line Sec.  514.80(b)(2).
    FDA believes that the commenter has simply misinterpreted the 
table. Section 514.80(b)(1) and (b)(2) are separate line items in the 
table. The confusion appears to be because the purpose column for Sec.  
514.80(b)(2) is blank because the subsequent three titles are 
subsections of Sec.  514.80(b)(2), i.e., Sec.  514.80(b)(2)(i) through 
(b)(2)(iii). Thus, a blank in the purpose column does not mean the 
preceding description applies. For clarity's sake, however, FDA has 
added the phrase ``See paragraphs below'' in place of the blank spaces.

III. Summary of the Final Rule

    FDA is withdrawing the interim final rule on its requirements for 
records and reports concerning experiences with approved new animal 
drugs (67 FR 5046) and is issuing this final rule. This final rule 
represents a modification of the withdrawn interim final rules. The 
modifications in the final rule include: Revising the definitions of 
``applicant'' and ``serious adverse drug experience;'' modifying the 
reporting requirement for summary reports of increased frequency of 
ADEs; clarifying what safety and efficacy records a nonapplicant versus 
an applicant must maintain; eliminating the requirement of submission 
of prepublication manuscripts relating to completed clinical trials; 
changing distributor's labeling so that the qualifying phrase that must 
precede the name and address of the distributor is as permitted by 
Sec.  201.1; and revising the section of the rule pertaining to 
distributor's signed statements to state that the distributor will 
promote the product only for use under the conditions stated in the 
approved labeling.

IV. Conforming Changes

    With the amendment of the animal drug regulations, certain 
revisions to parts 226, 510, and 514 (21 CFR parts 226, 510, and 514) 
and 21 CFR part 211 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.

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 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 final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612) and the 
Unfunded Mandates Reform Act (Public Law 104-4). The Office of 
Management and Budget (OMB) has determined that this final rule is a 
significant regulatory action subject to review under Executive Order 
12866. FDA also certifies in accordance with the Regulatory Flexibility 
Act 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, the Unfunded Mandates 
Reform Act does not require FDA to prepare a statement of costs and 
benefits for the final rule because it is not expected to result in any 
1-year expenditure that would exceed $100 million adjusted for 
inflation. The

[[Page 15362]]

current inflation-adjusted statutory threshold is about $110 million.
    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 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 ADE reports to be submitted by 
distributors is retained under the 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 that 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. In response to industry comments, FDA changed this 
requirement in the interim final rule to 5 years for all information. 
This would provide an additional opportunity for savings compared to 
the proposed rule. No additional comments were received on this issue, 
and the 5-year retention period has been retained in the final 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 decreased the 
reporting requirements in the interim final rule. No additional 
comments were received on this issue. The final rule requires reports 
of ADEs 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 about $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 would have required applicants to 
periodically review the incidence of ADEs 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. 
In response to comments, the final rule provides more flexibility to 
industry by allowing these reports to be submitted in the periodic drug 
experience reports rather than within the 15-day period. FDA expects to 
receive very few of these reports each year and estimates that the 
annual number will be between 1 and 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 to industry would be $1,400 annually. Periodic 
review of ADE reports, although on a less formal basis, is currently 
understood to be normal business practice.
    The net costs and benefits of this final rule, though 
indeterminate, are expected to be modest. FDA concludes that the 
impacts of the 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 that 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. This regulation is not 
expected to have a significant economic impact on these firms because 
the 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. A regulatory flexibility 
analysis, therefore, is not required.

VIII. Paperwork Reduction Act of 1995

    This 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

[[Page 15363]]

reviewing each collection of information.
    Title: Records and Reports Concerning Experience With Approved New 
Animal Drugs.
    Description: This final rule amends the provisions of the animal 
drug regulations concerning requirements for recordkeeping and reports 
concerning experience with approved new animal drugs. The information 
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 within 3 days of 
becoming aware the defect exists (new Sec.  514.80(b)(1)); a report 
that provides information on serious and unexpected adverse drug events 
and a followup report on such events (new Sec.  514.80(b)(2)); a 
summary report of increased frequency of ADEs (new Sec.  
514.80(b)(4)(v)); a report from nonapplicants, such as distributors, to 
applicants providing information on ADEs (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 reports; reports for 
advertising and promotional labeling, 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 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.
    All periodic reports must be submitted with Form FDA 2301, 
``Transmittal of Periodic Reports and Promotional Materials for New 
Animal Drugs'' (OMB control number 0910-0012). ADE reports must be 
submitted on Form FDA 1932, ``Veterinary Adverse Drug Reaction, Lack of 
Effectiveness, Product Defect Report'' (OMB control number 0910-0012).
    In the Federal Register of February 4, 2002, FDA invited comments 
on the interim final rule and the information collection requirements. 
Only one comment received pertained to information collection. That 
comment stated that the requirements under ``Multiple Applications'' do 
not appear to decrease but may increase the burden on the applicant. In 
particular, the comment questioned the requirement under Sec.  
514.80(c)(4) and requested clarification. The comment also voiced 
concern about an increased reporting burden due to the increasing 
number of approved applications for combinations of drugs for use in 
feeds since the implementation of the ADAA. Further complicating the 
reporting issue is that frequently there are nonapplicants involved in 
the marketing of these combinations. The comment stated that with the 
exception of ``promotion literature,'' there is rarely any other 
information to be reported, suggesting that the ``promotion 
literature'' be submitted to the application held by either party, 
i.e., the nonapplicants or applicant, and not the application approved 
for the use of the combination of drugs.
    In response, FDA notes that the provision of the regulation in 
question is currently codified under Sec.  510.300(b)(4)(ii). The 
current regulation and the proposal in the interim final rule are 
similar. There is no increase of the reporting burden. It is not the 
intention of FDA for the implementation of Sec.  514.80(c) to be 
different than the current requirement under Sec.  510.300(b)(4)(ii). 
Only information specific to a particular NADA/ANADA that is not common 
to all the applications must be included in the report for that 
particular NADA/ANADA, for example, labeling. With regard to the 
comment that there is an increased reporting burden due to the ADAA, 
increased reporting is due to the increased number of approved 
applications, and not due to different requirements. FDA consequently 
believes that this is a reasonable reporting requirement.
    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.

                                        RECORDS AND REPORTS CONCERNING EXPERIENCE WITH APPROVED NEW ANIMAL DRUGS
                                                     Table 1.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                  Annual
                                                                               No. of        [chyph]Frequency    Total Annual       Hours per      Total
                   21 CFR Section/Title/FDA Form No.                     [chyph]Respondents         per        [chyph]Responses  [chyph]Response   Hours
                                                                                              [chyph]Response
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.80(b)(2)(i)/Original 15-Day Alert Report/Form FDA 1932                       190               55.26           12,283                 1       12,283
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.80(b)(1)/3-Day Field Alert Report/ Form FDA 1932                             190                0.32               95                 1          95
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.80(b)(2)(ii)/Followup 15-Day Alert Report/Form FDA 1932                      190               17.90            6,007                 1       6,007
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.80(b)(3)/Nonapplicant Report/ Form FDA 1932                                  340                2.94            1,000                 1       1,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.80(b)(4)/Periodic Drug Experience Report/Form FDA 2301, and                  190                7.11            1,226                11       13,486
 514.80(c) Multiple Applications\2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.80(b)(4)(v)/Summary Report of Increased Frequency of Adverse Drug            190                1.58              300                 2         600
 Experience
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.80(b)(5)(i)/Special Drug Experience Report/ Form FDA 2301                    190                0.13               25                 2          50
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 15364]]

 
514.80(b)(5)(ii)/Advertising and Promotional Materials Report/ Form FDA          190                2.11              772                 2       1,544
 2301
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.80(b)(5)(iii)/Distributor's Statement Report/ Form FDA 2301                  530                0.14               56                 2         112
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                             35,177
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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 2.--Estimated Annual Recordkeeping Burden\1\
----------------------------------------------------------------------------------------------------------------
                                                               Annual
                                                   No. of     Frequency    Total Annual     Hours per    Total
                21 CFR Section                  Respondents      of      [chyph]Responses   Response     Hours
                                                              Response
----------------------------------------------------------------------------------------------------------------
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 Sec.   514.80(b)(1), (b)(2)(i), (b)(2)(ii), and (b)(3); Form FDA 1932.
\3\ Recordkeeping estimates for Sec.   514.80(b)(2)(iii), (b)(4), (b)(5), and (c); Form FDA 2301.

    Forms FDA 1932 and FDA 2301 for this collection of information are 
currently approved under OMB control number 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, CVM. The total 
annual response numbers are based on the 2000 fiscal year submission of 
reports to the Division of Surveillance, CVM. The numbers in tables 1 
and 2 of this document are total burden associated with this 
regulation. Section 514.80(b)(3) and (b)(4)(v) are new information 
collection requirements over the current requirements.
    The information collection provisions of this final rule have been 
submitted to OMB for review. FDA will publish a notice in the Federal 
Register announcing OMB's decision to approve, modify, or disapprove 
the information collection provisions in this final rule. An agency may 
not conduct or sponsor, and a person is not required to respond to, a 
collection of information unless it displays a currently valid OMB 
control number.

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.

0
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

0
1. The authority citation for 21 CFR part 211 continues to read as 
follows:

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


Sec.  211.198  [Amended]

0
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 ``in accordance with Sec. Sec.  
310.305 and 514.80 of this chapter.''

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

0
3. The authority citation for 21 CFR part 226 continues to read as 
follows:

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

0
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

0
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]

0
6. Section 510.300 Records and reports concerning experience with new 
animal drugs for which an approved application is in effect is removed.

[[Page 15365]]

Sec.  510.302  [Removed]

0
7. Section 510.302 Reporting forms is removed.

PART 514--NEW ANIMAL DRUG APPLICATIONS

0
8. The authority citation for 21 CFR part 514 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 360b, 371, 379e, 
381.

0
9. Section 514.3 is added 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.
    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 expected effectiveness).
    (3) An adverse event occurring in humans from exposure during 
manufacture, testing, handling, or use of a new animal drug.
    ANADA is an abbreviated new animal drug application including all 
amendments and supplements.
    Applicant is a person or entity who owns or holds on behalf of the 
owner the approval for an NADA or an ANADA, and is responsible for 
compliance with applicable provisions of the act and regulations.
    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.
    NADA is a new animal drug application including all amendments and 
supplements.
    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.
    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.
    Serious adverse drug experience is an adverse event that is fatal, 
or life-threatening, or requires professional intervention, or causes 
an abortion, or stillbirth, or infertility, or congenital anomaly, or 
prolonged or permanent disability, or disfigurement.
    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]

0
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]

0
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]

0
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''.

0
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:

------------------------------------------------------------------------
                                                   21 CFR Paragraph and
                    Purpose                               Title
------------------------------------------------------------------------
What information must be reported concerning     514.80(a)
 approved NADAs or ANADAs?                        Applicability.
------------------------------------------------------------------------
What authority does FDA have for requesting      514.80(a)(1).
 records and reports?
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  514.80(a)(2).
 and what reports filed with FDA?
------------------------------------------------------------------------
What is FDA's purpose for requiring reports?     514.80(a)(3).
------------------------------------------------------------------------
Do applicants of Type A medicated articles have  514.80(a)(4).
 to establish, maintain, and report information
 required under Sec.   514.80?
------------------------------------------------------------------------

[[Page 15366]]

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

[[Page 15367]]

 
What forms do I need?                            514.80(d) Reporting
What are Forms FDA 1932 and 2301?                 forms.
How can I get them?
Can I use computer-generated equivalents?
------------------------------------------------------------------------
How long must I maintain Form FDA 1932 and       514.80(e) Records to be
 records and reports of other required            maintained.
 information, i.e., how long do I need to
 maintain this information?
------------------------------------------------------------------------
What are the requirements for allowing access    514.80(f) Access to
 to these records and reports, and copying by     records and reports.
 authorized FDA officer or employee?
------------------------------------------------------------------------
How do I obtain Forms FDA 1932 and 2301?         514.80(g) Mailing
Where do I mail FDA's required forms, records,    addresses.
 and reports?
------------------------------------------------------------------------
What happens if the applicant fails to           514.80(h) Withdrawal of
 establish, maintain, or make the required        approval.
 reports?
What happens if the applicant refuses to allow
 FDA access to, and/or copying and/or verify
 records and reports?
------------------------------------------------------------------------
Does an adverse drug experience reflect a        514.80(i) Disclaimer.
 conclusion that the report or information
 constitutes an admission that the drug caused
 an adverse effect?
------------------------------------------------------------------------

    (a) Applicability. (1) Each applicant must establish and maintain 
indexed 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. Each 
nonapplicant must establish and maintain indexed and complete files 
containing full records of all information pertinent to safety or 
effectiveness of a new animal drug that is received or otherwise 
obtained by the nonapplicant. 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(e)) 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), (b)(4)(iv), and (b)(4)(v) 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.
    (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

[[Page 15368]]

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 completed clinical trials conducted by or for 
the applicant must be submitted no later than 1 year after completion 
of research. Supporting information is not to be reported.
    (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.
    (v) 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 evaluate the increased frequency of serious 
(expected or unexpected) adverse drug events at least as often as 
reporting of periodic drug experience reports. The applicant must 
report the increased frequency of serious (expected and unexpected) 
adverse drug events in the periodic drug experience report. 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 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 in a separate section within 
the periodic drug experience report.
    (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 labeling or 
advertisements 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 as permitted by the regulations 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 promote 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 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:

[[Page 15369]]

    (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 before 
use, may be used. Form FDA 1932 and Form FDA 2301 may be obtained on 
the Internet at http://www.fda.gov/cvm/forms/forms.html, 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 (click on ``Contact FDA,'' then 
``FDA Field Offices'').
    (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: March 21, 2003.
William K. Hubbard,
Associate Commissioner for Policy and Planning.
[FR Doc. 03-7475 Filed 3-28-03; 8:45 am]
BILLING CODE 4160-01-S