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Records and Reports Concerning Experience With Approved New Animal Drugs

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Information about this document as published in the Federal Register.

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Start Preamble

AGENCY:

Food and Drug Administration, HHS.

ACTION:

Interim final rule; opportunity for public comment.

SUMMARY:

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

DATES:

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

ADDRESSES:

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

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FOR FURTHER INFORMATION CONTACT:

William C. Keller, Center for Veterinary Medicine (HFV-210), Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-827-6641, or wkeller@cvm.fda.gov.

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SUPPLEMENTARY INFORMATION:

I. Introduction

In the Federal Register of December 17, 1991 (56 FR 65581), FDA (we) published a proposed rule (the proposed rule for records and reports) to revise § 510.300 (21 CFR 510.300) and to redesignate it as § 514.80 (21 CFR 514.80). This regulation implements section 512(l) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360b(l)) which provides that, following approval of an NADA or ANADA, applicants must establish and maintain records and make reports to the agency as prescribed by regulation or order. We proposed the revision in order to more clearly define the kinds of information to be maintained and submitted by the applicant and to revise the timing and content of certain reports to enhance the usefulness of the information.

After considering comments submitted in response to the proposed rule for records and reports, FDA is adopting the rule in modified form. The scope and coverage of this interim final rule differs in some respects from the proposed rule for records and reports. The proposed rule for records and reports covered NADAs, ANADAs, and medicated feed applications (MFAs). In contrast, the interim final rule covers only NADAs and ANADAs. The Animal Drug Availability Act of 1996 (ADAA) (21 U.S.C. 360b(a) and 360b(m)) amended the statutory provisions in the act regarding medicated feeds and eliminated MFAs. Therefore, the interim final rule does not address MFAs. However, the interim final rule retains reporting requirements for serious adverse drug experiences with feeds incorporating approved Type A medicated articles.

While the proposed rule for records and reports proposed to remove 21 CFR 510.310, which addressed records and reports for new animal drugs approved before June 20, 1963, we issued a final rule that revoked this provision in response to the Administration's “Reinventing Government Initiative” (61 FR 37680, July 19, 1996).

The proposed rule for records and reports followed a style and format similar to the human drug records and reports regulations in part 314 (21 CFR part 314). The interim final rule maintains a similar style and format, but removes many of the proposed records and reports requirements that are not necessary to monitor animal drugs.

In response to concerns over duplicate reporting, FDA has removed proposed § 514.82, which concerned records and reports from manufacturers, packers, labelers, and distributors other than the applicant. However, the agency has retained certain record and report requirements for nonapplicants (defined in new § 514.3(f)) in § 514.80(b) of this interim final rule.

For purposes of clarity, the agency has made some changes to the text and organization of the interim final rule. The following list provides examples of changes not intended to affect the substantive requirements of the rule:

  • All definitions in the proposed rule for records and reports have been consolidated in new § 514.3 Definitions. Specifically, definitions for the terms “applicant” and “nonapplicant” that appeared in text of the proposed rule for records and reports have now been moved to § 514.3.
  • Proposed § 514.80(a) discussed the requirements for “establish[ing] and maintain[ing] records and mak[ing] reports” in one paragraph. For easier reading, FDA has broken the paragraph down in this interim final rule to discuss the recordkeeping and reporting requirements separately.
  • New § 514.80(a)(2) discusses the reporting requirements in slightly greater detail than had been done in the proposed rule. This is intended to provide a road map of the requirements contained in other parts of the interim rule.
  • Final § 514.80(a)(5) was added to clarify that the records and reports referred to in this section are in addition to those required by the current good manufacturing practice regulations.
  • The interim final rule combines the proposed periodic adverse drug experience reports with the proposed annual reports (designated as § 514.80(d)(3) and (d)(4), respectively, in the proposed rule), because both reports require the same information. The combined report, which is now found at § 514.80(b)(4), is entitled “Periodic drug experience report” in the interim final rule.
  • Reporting requirements for reports of adverse drug experiences in the Start Printed Page 5047published literature were found in the proposed rule in the “General requirements” section (proposed § 514.80(e)). Similarly, reporting requirements for adverse drug experiences that occur during postapproval studies were also found in this section in the proposed rule. Because both of these requirements are part of the “Periodic drug experience report,” these sections have been moved in the interim final rule to § 514.80(b)(4) Periodic drug experience report. Specifically, the requirements for reports of adverse drug experiences in the published literature are now found in final § 514.80(b)(4)(iv)(B), and requirements for adverse drug experiences that occur during postapproval studies are now found in final § 514.80(b)(4)(iv)(C).

II. Response to Comments

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

Conversion Table 1.

Proposed Rule SectionInterim Final Rule Section
514.80(a) Applicability514.80(a)
514.80(b) Definitions514.3
514.80(c) Records to be maintained514.80(e)
514.80(d) Reporting requirements514.80(b)
514.80(d)(5)(iii) Statements of NADA approval statusNot included in interim final rule
514.80(e) General requirements514.80(c)
514.80(f) Reporting forms514.80(d) and 514.80(g)
514.80(g) Access to records and reports514.80(f)
514.80(h) Withdrawal of approval514.80(h)
514.81 Records and reports concerning experience with animal feeds bearing or containing new animal drugs for which an approved application is in effectNot included in interim final rule
514.82 Records and reports concerning experience with new animal drugs from manufacturers, packers, labelers, and distributors other than the applicant514.80(b)(3)

A. General Comments

(Comment 1) A number of comments questioned the need to change the existing regulation. These comments characterized the proposed changes as an unnecessary effort to make the animal drug regulations mimic the parallel regulations for human drugs. The comments emphasized the differences between human and veterinary medicine in treatment goals, dosing protocols, and evaluation of treatment responses. In light of these differences, the comments suggested that the record and reporting regulation for animal drugs should differ from the regulation for human drugs.

We agree that the regulations for human and animal drugs should differ in some areas. We changed the interim final rule in response to specific comments. Thus, the changes make the human and animal drug regulations similar but not identical.

(Comment 2) Some comments criticized our estimates of the annual reporting and recordkeeping burden. We estimated the proposed rule would require an additional 400 responses above the number required under the previous regulation from 200 businesses. The estimated increased total annual workload from the proposed rule was 200 hours, or approximately 1 hour per business. Representatives of the animal drug industry suggested that the added reporting burden would be 930 hours per respondent, with a total burden of 186,000 hours per year. This comment suggested that 500 hours per year were attributable to the proposed NADA-field alert report (proposed § 514.80(d)(1)), 90 hours per year to the proposed 15-day alert report followups (proposed § 514.80(d)(2)(ii)), 60 hours per year to the proposed periodic adverse drug experience reports (proposed § 514.80(d)(3)), and 280 hours per year to the proposed annual report (proposed § 514.80(d)(4)). The comments stated that the added burden was unjustified in the absence of any significant threat to the public health.

Our estimates of the annual reporting and recordkeeping burden in the proposed rule addressed only the increased burden resulting from the new provisions of the proposed regulation. The estimate did not include the workload resulting from previously existing provisions of the regulation. We have amended the estimated reporting and recordkeeping burden charts to reflect the total burden of the rule. Furthermore, our estimates are for the number of hours required to complete each response, not the number of hours per year per NADA holder as suggested in the comment. Thus, FDA's estimates are not directly comparable to those in the comment.

Additionally, the agency has made revisions in this interim final rule to provide for reduced reporting requirements under appropriate circumstances, thereby substantially reducing the reporting burden compared to the proposed rule. We have changed the reporting requirement for the 3-day NADA/ANADA field alert reports in the interim final rule (§ 514.80(b)(1)) so that applicants or nonapplicants must include only information pertaining to “product and manufacturing defects that may result in serious adverse drug events” instead of “any manufacturing defect” as was required in the proposed rule for records and reports (proposed § 514.80(d)(1)). This change will reduce the recordkeeping burden for this provision to a total of 60 hours.

Further, the periodic adverse drug experience report and annual report proposed in § 514.80(d)(3) and (d)(4) were combined into a single periodic drug experience report under § 514.80(b)(4). Finally, we agreed with comments that the requirement in § 514.80(d)(3) of the proposed rule for quarterly submissions of periodic drug experience reports for 3 years was excessive. Thus, the agency reduced this reporting requirement in § 514.80(b)(4) of the interim final rule to every 6 months for the first 2 years. The interim final rule requires 5 periodic drug experience reports within 3 years of approval; the proposed rule required 12 periodic drug experience reports within 3 years of approval.

We added provisions in interim final § 514.80(b)(4) that allow applicants to petition us to change the date of submission of yearly periodic drug experience reports or the frequency of reporting to intervals greater than annually. This provision will substantially reduce the number of periodic drug experience reports.

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

(Comment 3) Several comments characterized the phrase “whether or not considered drug-related” found in the proposed definition of “adverse drug experience” as being too broad in scope.

We agree that the definition is broad. However, we believe that such a broad definition is necessary in light of the agency's goal to encourage reporting that captures all possible adverse drug experiences. For example, it is often difficult to determine drug-relatedness in an individual case, but FDA, by seeing many reports, may see drug-relatedness that is not clear in individual instances. To prevent under-reporting and the possibility that rare or unexpected adverse drug reactions may be missed, the agency has decided to adopt the definition as proposed. However, in response to concerns over the implications of a broad definition, the agency has added a disclaimer in new § 514.80(i) which states that submission of a report or information does not necessarily constitute a conclusion or admission that a drug caused or contributed to an adverse effect.

(Comment 4) One comment suggested that reporting of adverse drug experiences be limited to “significant or meaningful events.”

We believe that limiting reporting as suggested could hinder postapproval surveillance because the significance of an event may not be apparent at the time of its occurrence. We desire to maintain and increase the availability and diversity of new animal drugs without compromising their safety and effectiveness. Postapproval reporting provides a source of vital information about the continued safety and effectiveness of a drug product over an extended period of time under field conditions. Therefore, we are maintaining the scope of the record and reporting requirements in this interim final rule.

(Comment 5) One comment questioned the rationale for defining “adverse drug experience” to include adverse events occurring in humans from exposure during manufacture, testing, handling, or use of a new animal drug. Several comments suggested that monitoring human health problems associated with exposure to new animal drugs is a responsibility of the Occupational Safety and Health Administration (OSHA) rather than FDA.

Under the act, we are required to consider the human health factor when approving new animal drugs. For example, FDA requires that appropriate warnings regarding potential adverse effects to human health be included in the labeling of new animal drugs. FDA's role in worker safety is complementary to OSHA's role. Furthermore, not all human exposure to new animal drugs would be through occupational exposure. We believe continued reporting of human adverse drug experiences as related to animal drugs is appropriate and important. This reporting provides the agency with the information it needs to fulfill its mandate to consider human health effects. Thus, the agency is retaining this element of the definition in the interim final rule.

(Comment 6) Comments asserted that the language used in proposed § 514.80(b)(1)(ii), (b)(1)(iii), and (b)(1)(iv) is inappropriate for new animal drugs. In particular, the comments questioned defining “adverse drug experience” in these sections to include an “adverse event occurring from animal drug overdose,” an “adverse drug event occurring from animal drug abuse,” and an “adverse event occurring from animal drug withdrawal.”

We agree that the phrases are not appropriate for animal drugs. These sections have been removed from the definition of “adverse drug experience” in new § 514.3(a) to more accurately reflect the practices of veterinary medicine and animal agriculture.

(Comment 7) Some comments questioned the phrase “failure of an animal drug product to produce its expected pharmacological action” in the definition of “adverse drug experience” in proposed § 514.80(b)(1)(v). Some of these comments suggested that the phrase be changed to say “unusual failure of an animal drug product * * * ” and noted that when animals are treated as a group rather than individually, the failure of some animals to respond is considered normal.

We agree that when groups of animals are treated, the failure of some individuals to respond to therapy can be considered normal. However, a perceived lack of effectiveness based on an unusual failure to respond to therapy is a valid reason to submit an adverse drug experience report. Failure of a drug to produce its expected pharmacological action (“lack of effectiveness”) may result in the underlying disease process progressing to a serious health problem. This health problem, therefore, is indirectly caused by the drug. The failure should be submitted in an adverse drug experience report. However, if the failure of some individuals to respond to therapy was expected (i.e., is listed in the labeling), this failure should be submitted in the periodic experience report. Thus, FDA has retained the phrase “failure * * * to produce its expected pharmacological * * * effect” in new § 514.3(a)(2).

The comments also asserted that clinical response rather than pharmacological action would more accurately describe the results being monitored.

We agree that clinical effect is another appropriate monitor in addition to lack of pharmacological action. Based on these comments, the language in new § 514.3(a)(2) has been revised to read “Failure of a new animal drug to produce its expected pharmacological or clinical effect (lack of effectiveness).”

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

(Comment 8) Some comments stated that monitoring and reporting an increased frequency in the rate of reported occurrences of any particular adverse drug experience is impractical in animal agriculture. One comment suggested that reporting of “increased frequency” should be limited to certain types of new animal drug products.

We believe that it is practical for applicants to monitor and report apparent increases in the number of reports concerning a specific type of adverse drug experience, after adjusting for any increase in drug use. Drug surveillance is important not just for identifying serious adverse drug reactions, but also for monitoring and accounting for any changes in the incidence of these same serious reactions. However, in response to concerns raised by the comments, we revised the definition of “increased frequency” in proposed § 514.80(b)(2) in new § 514.3(d) to limit required reporting to serious adverse drug events, expected or unexpected, after appropriate adjustment for drug exposure.

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

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

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

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

(Comment 10) Proposed § 514.80(b)(4) defined the term “serious,” as it relates to adverse drug experiences, to include “an adverse drug experience that is fatal, life-threatening, permanently disabling, requires hospitalization, or involves systemic drug or other intervention.” Several comments asserted that the phrase “or involves systemic drug or other intervention” as it appeared in this proposed section is too broad and the phrase “requires hospitalization” does not accurately reflect drug use in animal agriculture.

We agree with these comments. We have addressed these concerns by revising the definition of “serious adverse drug experience,” in new § 514.3(h). The definition is now more specific and reads “an adverse event that is fatal or life-threatening, requires professional intervention, or causes an abortion, stillbirth, infertility, congenital anomaly, prolonged or permanent disability, or disfigurement.” By including “requires professional intervention” (e.g., under a veterinarian's care) as a criterion, we reasonably limit the number of reports that have to be submitted under this portion of the regulation. The reference to hospitalization has been deleted in this interim final rule.

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

(Comment 11) Comments stated that the agency did not provide an explanation in the preamble to the proposed rule as to why the agency proposed to change the definition of “unexpected” (in the context of adverse drug experiences). Comments also stated that the existing definition of “unexpected” should be retained or the proposed new definition should be simplified.

FDA disagrees that the definition should be retained or simplified. In the preamble to the proposed rule, we did not explain why we proposed to change the definition of “unexpected.” The explanation is that the NADA or ANADA file is not publicly available, but the labeling is. Thus, “unexpected” adverse drug experiences should be provided in the labeling, so that anyone (not just someone with access to the NADA or ANADA file) can determine whether an event is unexpected.

Thus, we are keeping the definition as proposed. That definition, which is now found in new § 514.3(i), specifies that labeling, rather than the NADA or ANADA file, is the standard for comparison when deciding whether a reported event is an unexpected adverse drug experience.

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

(Comment 12) Many comments expressed concern that the proposed definitions for “product defect” and “manufacturing defect” were too broad because, under the definitions, FDA would require reporting of problems not associated with public health or animal safety.

We agree. We revised the two definitions to limit their scope to problems associated with public health or animal safety. For example, we have removed the following language, “observable or measurable deviation * * * from the typical physical and chemical characteristics expected for the animal drug product and its container” to prevent inclusion of factors that may affect physical appearance, but not public health or animal safety. For clarity, the two definitions have been combined in a single definition in new § 514.3(g). The revised definition also contains examples of product and manufacturing defects.

(Comment 13) One comment stated that the definition of “product defect” should be revised to specify only a situation when there is a confirmed deviation from standards in order to preclude submission of many reports that may prove to be unnecessary.

We disagree that the definition of suspected product defects should be revised to include only confirmed deviation from standards. We believe that if an applicant/nonapplicant had to confirm the deviation, it would be difficult for the applicant/nonapplicant to report such a defect within 3 working days of first becoming aware that a defect may exist, as required under new § 514.80(b)(1). However, we have revised the definitions of product defect and manufacturing defect to limit their scope (see comment 12 of this document). We have also narrowed the reporting requirement under § 514.80(b)(1) so that only those product and manufacturing defects that may result in serious adverse drug events must be reported.

During its consideration of this comment, we recognized a source of potential confusion in the proposed rule that is related to the issue raised by the comment. Specifically, “manufacturing defect” was defined in proposed § 514.80(b)(7) as “the manufacturing process is the cause of a product defect which is determined after investigation of a product defect complaint or a routine quality control procedure.” (Emphasis added). We did not intend for this definition to alter the requirement that manufacturing defects be reported to FDA within 3 working days of first becoming aware that such a defect may exist. To eliminate this potential confusion, we removed the phrase “which is determined after investigation of a product defect complaint or a routine quality control procedure” from the interim final rule's definition of “product defect/manufacturing defect” in new § 514.3(g).

(Comment 14) Some comments suggested that the phrase “or from the typical physical and chemical characteristics expected for the animal drug product and its container,” which appears in the proposed rule's definition of “product defect,” should be modified or deleted because it makes the definition too broad.

We agree that the phrase makes the definition too broad. We removed the phrase in this interim final rule.

(Comment 15) One comment argued that the proposed definition of “manufacturing defect” should be changed to specify distributed products only because the proposed definition would include reporting of all quality control or procedure problems.

FDA agrees that only those manufacturing defects that pertain to distributed products need be reported. The revised definition in new § 514.3(g) makes this clear by referring to “distributed” products.

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

(Comment 16) Some comments challenged the proposed 10-year retention period for records of all information concerning experience with approved new animal drugs. They argued that a 10-year retention period is unnecessary and burdensome. They suggested that the retention time be reduced to 1 or 2 years.

FDA agrees that 10 years may be an unnecessarily long time to retain these records of all information. Accordingly, the agency has amended the record retention period from 10 to 5 years. New § 514.80(e) requires retention of records of all information for 5 years after the date of submission. FDA believes that a 5-year retention period is adequate and necessary to ensure that records exist for a sufficient time to permit us to evaluate events that occur at limited frequency.

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

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

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

(Comment 18) One comment suggested that the requirement for reporting product and manufacturing defects should be limited to significant problems relevant to the drug's safety or efficacy.

FDA agrees and has revised the reporting requirements in new § 514.80(b)(1) so that only those product and manufacturing defects that may result in serious adverse drug events must be reported.

(Comment 19) Some comments expressed a concern that the proposed rule would require duplicate reporting of manufacturing defects to FDA's district offices and Center for Veterinary Medicine (CVM).

We did not intend to require duplicate reporting. The agency believes this was clear under proposed § 514.80(d)(1), which stated that reports should be submitted “to the FDA district office that is responsible for the facility involved.” Thus, we are largely retaining this language. However, because some areas of the United States are covered by a local FDA resident post rather than a district office, the agency is modifying the interim final rule to reflect this. New § 514.80(b)(1) states that “[t]he applicant * * * must submit the report to the appropriate FDA district office or local FDA resident post within 3 working days of first becoming aware that a defect may exist.” To further clarify where specific reports must be sent, we have added new § 514.80(g) Mailing addresses to this interim final rule.

(Comment 20) One comment suggested extending the time required for submitting the proposed NADA field alert report from 3 to 10 days.

We believe that 3 working days are sufficient time to investigate the existence of a reportable event and make an initial report. Thus, we have retained this timeframe for 3-day NADA/ANADA field alert reports in new § 514.80(b)(1). The agency notes that a complete written report is not required within the 3-day period. If, as specified in § 514.80(b)(1), the information is provided by telephone or other telecommunication means within 3 days, followed by prompt (within a timeframe agreed upon at the time of the initial telecommunication) written followup on Form FDA 1932 “Veterinary Adverse Drug Reaction, Lack of Effectiveness, Product Defect Report,” FDA will consider the 3-day requirement to have been met.

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

(Comment 21) Several comments interpreted proposed § 514.80(d)(2)(ii) as requiring repeated followup reports at 15-day intervals. These comments questioned the need for such followup and proposed a single followup once all the information was collected within 15 days or after collection of the information.

The intent of the regulation is not to require multiple followup reports. We believe that most adverse drug experiences can be documented with either a single initial report or an initial report and a followup report if significant new information is received. To clarify this intent, § 514.80(b)(2)(ii) of the interim final rule has been revised to read: “* * *[if] this investigation reveals significant new information, a followup report must be submitted within 15 days of receiving such information.” A 3-month period is designated as the reasonable time needed to obtain such information. If additional information is sought but not obtained within 3 months of the initial report, a followup report is required describing the steps taken and why additional information was not obtained.

(Comment 22) Proposed § 514.80(d)(2) required that the initial 15-day alert report be submitted using Form FDA 1932. One comment suggested that the Form FDA 1932 be submitted only at the conclusion of the investigation of the adverse drug experience. The comment suggested that the initial report could be less formal.

We disagree with these suggestions. A standardized reporting format is essential for the efficient collection and processing of useful data. Thus, FDA has retained the required use of the Form FDA 1932 for the 15-day NADA/ANADA alert report in this interim final rule.

(Comment 23) Several comments suggested that 15-day alert reports of adverse drug experiences be limited to events judged to be “drug-related” by the applicant.

We disagree with this concept. For FDA to determine drug-related effect, applicants must submit all reports of adverse drug experience so that the agency can evaluate the data in an unbiased manner. FDA maintains a computer data base of reported information. The data base is evaluated for trends or patterns of reports, and the trends are further investigated. Limiting reporting to “drug-related” events could hamper the discovery of uncommon or unexpected adverse drug experiences.

To alleviate concerns that reporting automatically implicates the drug, we added new § 514.80(i). This section provides that the adverse drug experience report “will be without prejudice and does not necessarily reflect a conclusion that the report or information constitutes an admission that the drug caused or contributed to an adverse event.”

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

(Comment 24) Several comments criticized proposed § 514.80(d)(3), asserting that the proposed requirements for periodic drug experience reports are inappropriate, unnecessary, and burdensome in requiring quarterly reports for 3 years. Two comments recommended 6-month reports for 2 years.

We agree with many of the comments and revised the provisions regarding periodic drug experience reports. We have combined the periodic adverse drug experience report requirements with annual reporting requirements into new section, § 514.80(b)(4). The frequency of reporting for new approvals has been changed from the proposed schedule of “quarterly intervals for 3 years from the date of approval and annually thereafter” (as it appeared in proposed § 514.80(d)(3)) to “every 6 months for the first 2 years after approval of an NADA or ANADA, and yearly thereafter.” (See new § 514.80(b)(4).) In light of this change, we wish to clarify the reporting requirement for the periodic drug experience reports. We are requiring that these periodic drug experience reports contain data and information for the full reporting period. To facilitate this reporting requirement, we will allow sponsors to file 6-month periodic drug experience reports within 30 days after the end of the 6-month reporting period. With regard to the yearly periodic drug experience report, these Start Printed Page 5051must be submitted within 60 days of the anniversary date of the approval of the NADA or ANADA.

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

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

(Comment 25) Two comments noted that the phrase “quantities distributed for foreign use” in proposed § 514.80(d)(4)(I) is unclear, and that the collection of the data would be unreliable and difficult to obtain.

The phrase, which is now in new § 514.80(b)(4)(i), has been revised to read “quantities distributed domestically and quantities exported.” We believe that the data are obtainable (currently, CVM receives such data from applicants) and, if properly collected, should be reliable. The data will be useful in CVM's postmarketing surveillance activities, such as the adverse drug experience program.

(Comment 26) Four comments objected to the requirement in proposed § 514.80(d)(4)(ii) that applicants provide a summary of any changes in the labeling. Comments argued that FDA already has this information on file.

We believe that this requirement does not impose a significant new reporting burden, yet provides us with very useful information. The requirement is necessary to ensure that all labeling changes, including those recently made or not previously reported, are documented. By providing a summary of any changes in the labeling, applicants will facilitate CVM's review of periodic drug experience reports. Therefore, we retained the requirement in new § 514.80(b)(4)(ii).

(Comment 27) Several comments questioned the need for providing the date of implementation of manufacturing and control changes, required under proposed § 514.80(d)(4)(iv). The comments described the requirement as an unnecessary paperwork burden on both industry and Government. One comment noted that the requirement was redundant because “a chronological list of changes is available upon field inspection.”

We disagree with these comments. The date when a change is implemented is important to identify the production batches that may be affected by the change. This is important for various reasons, including allowing reviewers to compare data generated at different times to determine if there are any changes or trends in product quality. However, section 116 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) (21 U.S.C. 356a) describes reporting procedures and requirements for making major and other manufacturing changes to an approved application. Under FDAMA, we proposed to revise § 514.8 (21 CFR 514.8), the provisions for supplemental applications for changes in the manufacturing of animal drugs, and specify the reporting requirements for manufacturing changes. (See 64 FR 53281, October 1, 1999.) Therefore, we removed the requirement described in proposed § 514.80(d)(4)(iv) from this interim final rule.

(Comment 28) Proposed § 514.80(d)(4)(v)(C) required applicants to submit descriptions of completed clinical trials conducted by or known to the applicant. Some comments questioned whether this requirement would result in possible duplicate reporting of clinical trial information or adverse drug experiences associated with an investigational new animal drug. Also, the difference between the terms “completed” and “concluded” was questioned in terms of when the study was to be reported to FDA. Proposed § 514.80(d)(4)(v)(C) stated: “A study is considered completed no later than 1 year after it is concluded.”

We did not intend to require duplicate reporting. To make this explicit, we renamed the section “Nonclinical laboratory studies and clinical data not previously reported,” in new § 514.80(b)(4)(iii). We included the phrase “not previously reported” in the title to clarify that duplicate reporting is not required. To eliminate confusion over the difference between “completed” and “concluded,” new § 514.80(b)(4)(iii)(C) now states that “a study must be submitted no later than 1 year after completion of research.”

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

(Comment 29) Several comments suggested that the requirements regarding submission of advertisements and promotional labeling in § 510.300 were adequate. These comments further suggested that FDA should retain these requirements rather than adopting the new requirement in proposed § 514.80(d)(5)(I). In addition, the comments challenged as unnecessary and burdensome the requirement that a copy of the product labeling be included in the submission.

The agency believes that the language in new § 514.80(b)(5)(ii) is an improvement over § 510.300 because it clarifies and delineates the requirements for advertisements and promotional labeling for both prescription and over-the-counter drugs. However, FDA agrees that samples of a product's current labeling need not accompany each submission of promotional material. Accordingly, we removed this requirement from the regulation.

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

(Comment 30) Comments asserted that the timing of submission of the distributor statement and labeling as established under proposed § 514.80(d)(5)(ii) was unclear because the preamble to the proposed rule suggested submission with the annual report, but the proposed rule required submission “[a]t the time of initial distribution.”

We clarified the timing of submission in the interim final rule. In new § 514.80(b)(5)(iii), the distributor's statement and samples of labeling are to be submitted as a special drug experience report “at the time of initial distribution of a new animal drug product by a distributor.”

(Comment 31) Comments also questioned the meaning of the term “own-label (private label) distributor” as it appeared in proposed § 514.80(d)(5)(ii).

We agree that the proposed language was unclear. We removed the phrase “own-label (private label).” The wording in new § 514.80(b)(5)(iii)(A) reads, “distributor's current product labeling.”

(Comment 32) One comment asserted that the information required in distributor statements are business arrangements which should be kept on file by applicants and not be submitted to FDA.

We disagree with this comment. The distributor statements are kept on file at FDA to provide cross-reference information for the drug listing process. The statements may also be important to us during an establishment inspection.

P. Statements of NADA Approval Status

(Comment 33) Proposed § 514.80(d)(5)(iii) codified the reporting requirements that applicants needed to comply with before they could add a statement of NADA approval status to Start Printed Page 5052the product labeling. Before the enactment of FDAMA, the act expressly prohibited the use of approval status statements on the labeling of human drugs under section 301(l) of the act (21 U.S.C. 331(l)), but did not prohibit the use of such statements on new animal drug labeling. Section 421 of FDAMA struck section 301(l) from the act, thereby lifting the prohibition for adding such statements to human drug labeling. Because the agency has decided that it will implement this revision of the act by providing uniform guidance concerning product approval status statements for both human and animal products, we determined that it would be inappropriate to retain proposed § 514.80(d)(5)(iii) in this interim final rule.

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

(Comment 34) Proposed § 514.80(d)(5)(iv) provided that “[u]pon written request, FDA may require that the applicant submit the reports required under this section at different times than those stated.” One comment suggested that FDA should have retained § 510.300(b)(5) rather than adopting proposed § 514.80(d)(5)(iv). This comment interpreted the language in § 510.300(b)(5) as ensuring that special reports are based on a “mutually agreed upon need and not a mere increase in frequency in reporting.”

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

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

(Comment 35) Several comments requested clarification of proposed § 514.80(e)(1) which states: “If a report refers to more than one animal drug marketed by an applicant, the applicant shall submit the report to the application for each animal drug listed in the report. The report is required to identify all the applications to which the report applies.” Comments questioned whether this was applicable to combination drug products and whether FDA intended the applicant to file these reports with all dosage forms of the drug or just with the dosage form involved in the adverse experience report.

This section was intended to refer to periodic reporting requirements when an applicant has more than one NADA or ANADA containing a particular active ingredient. FDA has replaced the language proposed in § 514.80(e)(1) with language almost identical to that contained in § 510.300(b)(4)(ii). FDA has redesignated the general requirements section as § 514.80(c) in the interim final rule, and has further clarified the requirements needed to implement this section. The clarification provided for in the interim final of § 514.80(c)(1) through (c)(4) reflects the current reporting practice. If applicable, the applicant must do the following: (1) State when a report applies to multiple applications and identify all related applications; (2) ensure that the primary application contains a list of all related applications; (3) submit a completed Form FDA 2301, “Transmittal of Periodic Reports and Promotional Materials for New Animal Drugs,” to the primary application, and to each related application that references the primary application and corresponding submission date; and (4) if there is information that is unique to a particular application, the information must be submitted in the report for that particular NADA and/or ANADA.

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

(Comment 36) Several comments questioned the scope of the published literature that needed to be provided to FDA. The comments asserted that only publications from current scientific journals (excluding those listed in 21 CFR 510.95) and only substantive articles should be required. The comments stated that obscure foreign journals with translations may require extended time periods to obtain. Section 314.80(d)(1) and (d)(2) of the human drug regulations were mentioned as examples of appropriate limitations.

We believe that the scope of published literature on reports of adverse drug experiences should be kept broad. In recent years, extensive searches of literature data bases have become quicker, more practical, and more economical to perform. If the agency were to narrow the scope of these searches, potentially valuable information might not be submitted. However, in an effort to reduce the burden of this requirement upon applicants, the agency has revised the requirement. Under proposed § 514.80(e)(2), applicants would have been required to submit actual copies of all published articles. We revised this requirement (new § 514.80(b)(4)(iv)(B)) such that applicants generally need only include a bibliography of pertinent references in the report.

(Comment 37) Several comments suggested that the requirement to provide photocopies of published articles was impractical because of copyright restrictions of publishers.

We are now able to access abstracts and articles through electronic data bases via the Internet. This development has eliminated the need for applicants to include copies of abstracts or articles in each report. Thus, as stated above, proposed § 514.80(e)(2) has been revised. Under the new § 514.80(b)(4)(iv)(B), an applicant will be required to provide a full text copy of a publication only upon FDA's request.

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

(Comment 38) Two comments suggested that reporting of adverse experiences in postapproval studies as required in proposed § 514.80(e)(3) was redundant and might result in duplicate reporting.

In response to these comments, the language in new § 514.80(b)(4)(iv)(C) has been changed to specify “[r]eports of adverse drug experiences in studies or trials not previously reported either individually or as part of an NADA/ANADA * * *” (Emphasis added).

U. Reporting Forms (New § 514.80(d))

(Comment 39) One comment stated that Form FDA 1932 is poorly suited for reports of product defects or human exposure to animal drugs. The suggestion was made that FDA modify the form or allow alternative reporting formats.

We believe that Form FDA 1932 and Form FDA 2301 are appropriate vehicles for reporting. Thus, the agency is retaining the requirement that these forms be used where designated in the interim final rule.

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

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

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

FDA received several comments on the proposed regulation concerning the portion of the regulation dealing with MFAs. However, the ADAA amended the statutory provisions in the act regarding medicated feeds. Type A medicated articles are new animal drugs that may be used to make medicated feeds. Feed mills use Type A medicated articles to make medicated feeds. Prior to the passage of the ADAA, sponsors were required to obtain approval of NADAs for Type A medicated articles, and feed mills that made medicated feeds were required to obtain approval of an MFA for each medicated feed manufactured at each site before they could legally manufacture the medicated feed. The ADAA eliminated this requirement regarding MFAs for feed mills, but not the requirement for sponsors to obtain approval of NADAs for Type A medicated articles.

Revisions to the MFA regulations to reflect the provisions of ADAA were the subject of a final rule that published in the Federal Register of November 19, 1999 (64 FR 63195). Because of these revisions, the agency has removed the requirements for MFAs from the final rule. Proposed § 514.81 described the records and reports requirements for holders of MFAs. There are no longer holders of MFAs. However, the agency still needs information regarding approved Type A medicated articles incorporated in animal feeds. Under the final rule, this information is provided by the holder of the NADA for the Type A medicated feed, and, as stated in new § 514.80(a)(4), the record and report requirements found in new § 514.80(b)(1), (b)(2), and (b)(4)(iv) are applied to any approved Type A medicated article incorporated in animal feeds. The agency will address any remaining issues regarding records and reports for medicated feeds at a later date in a new proposed rule, if necessary.

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

(Comment 42) Proposed § 514.82 established requirements for records and reports concerning experience with new animal drugs from manufacturers, packers, labelers, and distributors other than the applicant. Several comments stated that requiring a nonapplicant to report to FDA is neither efficient nor necessary, because it would result in duplicate reporting. One comment stated that an applicant may be a subsidiary of a parent firm.

We agree with these comments and have deleted the proposed section from the regulations. However, the agency has retained certain record and report requirements for nonapplicants (new § 514.3(f)) in new § 514.80(b). The interim final rule specifies under new § 514.80(b)(3) that the nonapplicant is required to provide necessary information to the applicant. The applicant is required to report to FDA. The nonapplicant must retain certain records concerning events as provided in new § 514.80(b)(3). The nonapplicant may choose to forward a copy of the report to FDA, but this action would be voluntary.

III. Conforming Amendments

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

IV. Request for Comments

Interested persons may submit to the Dockets Management Branch (address above) written or electronic comments on new information regarding this interim final rule by April 5, 2002. Two copies of any comments are to be submitted, except that individuals may submit one copy. Comments are to be identified with the docket number found in brackets in the heading of this document. Received comments may be seen in the Dockets Management Branch between 9 a.m. and 4 p.m., Monday through Friday. The agency believes it is in the public interest to have the regulations in place while, at the same time, it solicits public comments on new issues. The agency will not consider any comments that have been previously considered during this rulemaking.

V. Environmental Impact

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

VI. Federalism

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

VII. Analysis of Impacts

FDA has examined the impacts of the interim final rule under Executive Order 12866 and has determined that it does not constitute an economically significant rule, as defined in the Executive order. FDA also certifies in accordance with the Regulatory Flexibility Act (5 U.S.C. 601-612) that this rule will not have a significant economic impact on a substantial number of small entities, and therefore, a regulatory flexibility analysis is not required. Further, since this rule will not impose any mandates on other governmental entities and will result in the expenditure of less than $100 million by the private sector, FDA does not need to prepare additional analyses under the Unfunded Mandates Reform Act.

The regulation is intended to clarify and simplify recordkeeping requirements while improving the protection of public and animal health. The revisions in the reporting requirements are expected to provide savings through lower recordkeeping costs in some areas while imposing small cost increases due to requirements Start Printed Page 5054for recordkeeping of more useful information.

In the rule, the term “applicant” is limited to the holder of an approved application (NADA or ANADA) and does not include every firm whose name appears on product labeling, as the regulations previously provided. A nonapplicant is required to send copies of necessary information to the applicant who would then combine all information received, whether from one or several sources, and submit a single report to FDA. This change would reduce paperwork requirements because firms would be required to submit fewer reports. Also, those reports should provide for a more comprehensive reporting of all required information.

The current requirement for adverse drug experience reports to be submitted by distributors under proposed § 514.82 is retained under the interim final rule in § 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 § 510.300(f) that applies to a small number of firms that would not routinely be expected to receive such information. The restatement is intended to clearly state that any such information received is required to be reported to FDA, either directly or through the applicant. However, only one party would be required to file the report.

The revised regulations amend the language of the regulations to clarify current practices. The conformity of reporting requirements for animal drugs and human drugs may simplify the process for firms that manufacture both kinds of products. No added costs are expected for those firms who only manufacture new animal drug products.

In the past, FDA has required that records and reports be retained for an indefinite period. The proposed rule provided for a retention period of 10 years. FDA has changed this requirement to 5 years for all information, in response to industry comments. This would provide an additional opportunity for savings compared to the proposed rule. Since the current average length of time which records are kept is unknown, it is possible that there will be a small net cost due to this provision, even though the reporting requirements are clarified for easier compliance and administration.

The previously existing regulation required reports concerning newly approved NADAs and ANADAs every 6 months for the first year and annually thereafter. The proposed rule for records and reports would have required submission of such reports at quarterly intervals for 3 years following approval. FDA agrees with comments from industry that the proposed rule's requirement of reports at quarterly intervals for 3 years following approval was unnecessary, and the agency has decreased the reporting requirements in the interim final rule. The interim final rule requires reports of adverse drug experiences to be submitted every 6 months for 2 years and annually thereafter.

The net change from the previous regulation requires one additional report in the second year. FDA estimates that it approves 30 NADAs annually. FDA estimates that 13.6 hours are required to establish and maintain the drug experience data, as well as write the report. Total hours required for this provision are estimated at 408. At a middle manager's estimated total wage rate of $35 per hour, this provision would cost $14,280 annually. Moreover, applicants may petition for lengthier report intervals. FDA will provide for reporting at intervals longer than 1 year when justified based on current experience or manufacturing and marketing status. The expected number of petitions for reporting at intervals greater than 1 year is difficult to estimate because it depends on the extent to which each individual company wishes to qualify for this provision. The net result of these two provisions may be either a very small cost or savings to each firm.

The interim final rule requires applicants to periodically review the incidence of adverse drug experiences and report any significant increase in the frequency to FDA as soon as possible or within 15 working days of determining a significant increase in frequency exists. FDA expects to receive very few of these each year and estimates the annual number at 1 to 20. These reports would not be expected to take more than 1 to 2 hours of a manager's time, and the high-end estimated cost would be $1,400 annually. Periodic review of adverse drug experience reports, although on a less formal basis, is already understood to be normal business practice.

The net costs and benefits of this interim final rule, though indeterminate, are expected to be modest. FDA concludes that the impacts of the interim final rule do not qualify it as an economically significant rule as defined under Executive Order 12866.

The Regulatory Flexibility Act, as amended (5 U.S.C. 601-612), allows for a waiver of the regulatory flexibility analysis if an agency certifies there will not be a significant impact on a substantial number of small entities as a result of a rule, as well as provides the factual basis for such a certification. The Small Business Administration definition of a small business in this industry category is limited to those firms with less than 750 employees. It is expected that a substantial number of the firms which will be subject to the new recordkeeping and reporting requirements will meet the definition of small businesses. FDA estimates that from 1 to 13 of the approximately 30 NADA and ANADA approvals in 1999 may have been from small businesses. Using the upper end of this range, about 42 percent of the firms receiving approval annually would be subject to the new recordkeeping and reporting requirements. Although these firms constitute a substantial number of firms being granted an approval each year, this proposal is not expected to have a significant economic impact on these firms, because the interim final rule is intended to simplify and clarify current recordkeeping and reporting requirements. The net costs and benefits on each small firm are expected to be modest. Accordingly, FDA certifies in accordance with the Regulatory Flexibility Act (5 U.S.C. 601-612) that this rule will not have a significant economic impact on a substantial number of small entities, and therefore, a regulatory flexibility analysis is not required.

VIII. Paperwork Reduction Act of 1995

This interim final rule contains information collection provisions that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-3520). A description of these provisions is given below. Included is the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing each collection of information.

Title: Records and Reports Concerning Experience With Approved New Animal Drugs

Description: This interim final rule amends the provisions of the animal drug regulations concerning requirements for recordkeeping and reports of adverse experiences and other information relating to approved new animal drugs. The information Start Printed Page 5055contained in the reports required by this rule enables FDA to monitor the use of new animal drugs after approval and to ensure their continued safety and efficacy. The reporting requirements include: A report that provides information on product and manufacturing defects that may result in serious adverse drug events (new § 514.80(b)(1)); a report that provides information on serious, unexpected adverse drug events and a followup report on such events (new § 514.80(b)(2)); a summary report of increased frequency of adverse drug experiences (new § 514.80(b)(2)(iii)); a report from nonapplicants, such as distributors, to applicants providing information on adverse drug experiences (new § 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 § 514.80(b)(4)); and other reports that include special drug experience report; reports for advertising and promotional material, and reports for distributor statements (new § 514.80(b)(5)). These reports must be kept for 5 years (new § 514.80(e)).

The interim final rule strengthens the current reporting system by requiring periodic reports every 6 months for the first 2 years following initial approval of an application rather than just for the first year following initial approval. The increased burden on applicants amounts to one additional periodic report. While greater than the reporting burden in the previous rule, this burden is less than that of the proposed rule which would have required quarterly periodic reports for 3 years following initial approval.

The reporting burden of the proposed rule has been reduced further in other ways. In the interim final rule, the report pertaining to product and manufacturing defects must include only information on defects “that may result in serious adverse drug events” (new § 514.80(b)(1)) rather than information on all manufacturing defects, as in the proposed rule. Additionally, the proposed rule required a periodic adverse drug experience report and an annual report, whereas the interim final rule has combined these reports into a single periodic drug experience report (new § 514.80(b)(4)). The interim final rule also reduces the reporting requirements of the proposed rule by eliminating proposed § 514.82, which required records and reports from manufacturers, packers, labelers, and distributors other than the applicant. The recordkeeping requirements of the proposed rule have also been reduced in the interim final rule by changing the required period of time records must be kept from 10 to 5 years (new § 514.80(e)).

All periodic reports must be submitted with Form FDA 2301, “Transmittal of Periodic Reports and Promotional Materials for New Animal Drugs” (OMB Control No. 0910-0012). Adverse drug experience reports must be submitted on Form FDA 1932, “Veterinary Adverse Drug Reaction, Lack of Effectiveness, Product Defect Report” (OMB Control No. 0910-0012).

Description of Respondents: Applicant respondents are sponsors of approved NADAs and ANADAs. Nonapplicant respondents are those, other than the applicant, involved in manufacturing, processing, packing, labeling, or distributing new animal drugs.

Although the proposed rule of December 17, 1991 (56 FR 65581), provided a 60-day comment period under the PRA of 1980 and this interim final rule responds to the comments received; FDA is providing an additional opportunity for public comment under the PRA of 1995, which became effective after the publication of the proposed rule and applies to this interim final rule. Therefore, FDA now invites comments on: (1) Whether the proposed collection of information is necessary for the proper performance of FDA's functions, including whether the information will have practical utility; (2) the accuracy of FDA's estimate of the burden of the proposed collection of information, including the validity of the methodology and assumptions used; (3) ways to enhance the quality, utility, and clarity of the information to be collected; and (4) ways to minimize the burden of the collection of information on respondents, including through the use of automated collection techniques, when appropriate, and other forms of information technology.

At the close of the 60-day comment period, FDA will review the comments received, revise the information collection provisions as necessary, and submit these provisions to OMB for review and approval. FDA will publish a notice in the Federal Register when the information collection provisions are submitted to OMB and provide an opportunity for public comment to OMB at that time. Prior to the effective date of this interim final rule, FDA will publish a notice in the Federal Register of OMB's decision to approve, modify, or disapprove the information collection provisions. An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a valid OMB control number.

RECORDS AND REPORTS CONCERNING EXPERIENCE WITH APPROVED NEW ANIMAL DRUGS

Table 2.—Estimated Annual Reporting Burden1

21 CFR Section/Title/FDA Form No.No. of RespondentsAnnual Frequency per ResponseTotal Annual ResponsesHours per ResponseTotal Hours
514.80(b)(2)(i)/Original 15-Day Alert Report/Form FDA 193219055.2612,283112,283
514.80(b)(1)/3-Day Field Alert Report/ Form FDA 19321900.3295195
514.80(b)(2)(ii)/Followup 15-Day Alert Report/Form FDA 193219017.906,00716,007
514.80(b)(2)(iii)/Increased Frequency 15-Day Alert Report1901.583002300
514.80(b)(3)/Nonapplicant Report/ Form FDA 19323402.941,00011,000
514.80(b)(4)/Periodic Drug Experience Report/Form FDA 2301, and 514.80(c) Multiple Applications21907.111,2261113,486
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514.80(b)(5)(i)/Special Drug Experience Report/ Form FDA 23011900.1325250
514.80(b)(5)(ii)/Advertising and Promotional Materials Report/ Form FDA 23011902.1177221,544
514.80(b)(5)(iii)/Distributor's Statement Report/ Form FDA 23015300.14562112
Total34,877
1 There are no capital costs or operating and maintenance costs associated with this collection of information.
2 The reporting burden for § 514.80(b)(4)(iv)(A) is included in the reporting burden for § 514.80(b)(2)(i).

Table 3.—Estimated Annual Recordkeeping Burden1

21 CFR SectionNo. of RespondentsAnnual Frequency of ResponseTotal Annual ResponsesHours per ResponseTotal Hours
514.80(e)253028.2219,3850.59,693
514.80(e)35304.062,37910.3524,623
Total34,316
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 §§ 514.80(b)(1), 514.80(b)(2)(i), 514.80(b)(2)(ii), and 514.80(b)(3); Form FDA 1932.
3 Recordkeeping estimates for §§ 514.80(b)(2)(iii), 514.80(b)(4), 514.80(c), and 514.80(b)(5); Form FDA 2301.

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

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Therefore, under the Federal Food, Drug, and Cosmetic Act and under authority delegated to the Commissioner of Food and Drugs,

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PART 211—CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS

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1. The authority citation for

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

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2. Section 211.198

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

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3. The authority citation for

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

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

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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 § 514.80 of this chapter.

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PART 510—NEW ANIMAL DRUGS

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5. The authority citation for

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

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6. Section 510.300

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7. Section 510.302

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PART 514—NEW ANIMAL DRUG APPLICATIONS

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8. The authority citation for

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Authority: 21 U.S.C. 360b, 371.

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9. Section 514.3 is added to subpart A to read as follows:

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Definitions.

The definition and interpretation of terms contained in this section apply to those terms as used throughout subchapter E.

(a) Adverse drug experience is any adverse event associated with the use of a new animal drug, whether or not considered to be drug related, and whether or not the new animal drug was used in accordance with the approved labeling (i.e., used according to label directions or used in an extralabel manner, including but not limited to different route of administration, different species, different indications, or other than labeled dosage). Adverse drug experience includes, but is not limited to:

(1) An adverse event occurring in animals in the course of the use of an animal drug product by a veterinarian or by a livestock producer or other animal owner or caretaker.

(2) Failure of a new animal drug to produce its expected pharmacological or clinical effect (lack of effectiveness).

(3) An adverse event occurring in humans from exposure during manufacture, testing, handling, or use of a new animal drug.

(b) ANADA is an abbreviated new animal drug application including all amendments and supplements.

(c) Applicant is a person who owns a new animal drug application or ANADA.

(d) Increased frequency of adverse drug experience is an increased rate of occurrence of a particular serious adverse drug event, expected or unexpected, after appropriate adjustment for drug exposure.

(e) NADA is a new animal drug application including all amendments and supplements.

(f) Nonapplicant is any person other than the applicant whose name appears on the label and who is engaged in manufacturing, packing, distribution, or labeling of the product.

(g) Product defect/manufacturing defect is the deviation of a distributed product from the standards specified in the approved application, or any significant chemical, physical, or other change, or deterioration in the distributed drug product, including any microbial or chemical contamination. A manufacturing defect is a product defect caused or aggravated by a manufacturing or related process. A manufacturing defect may occur from a single event or from deficiencies inherent to the manufacturing process. These defects are generally associated with product contamination, product deterioration, manufacturing error, defective packaging, damage from disaster, or labeling error. For example, a labeling error may include any incident that causes a distributed product to be mistaken for, or its labeling applied to, another product.

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

(i) Unexpected adverse drug experience is an adverse event that is not listed in the current labeling for the new animal drug and includes any event that may be symptomatically and pathophysiologically related to an event listed on the labeling, but differs from the event because of greater severity or specificity. For example, under this definition hepatic necrosis would be unexpected if the labeling referred only to elevated hepatic enzymes or hepatitis.

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10. Section 514.8

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(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 § 514.80(b)(5)(iii) are met before putting such a change into effect.

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11. Section 514.11

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[Amended]
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12. Section 514.15

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13. Section 514.80 is added to subpart B to read as follows:

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Records and reports concerning experience with approved new animal drugs.

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

PurposeParagraph and Title
What information must be reported concerning approved NADAs or ANADAs?514.80(a) Applicability
What authority does FDA have for requesting 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?514.80(a)(1)
What records must be established and maintained and what reports filed with FDA?514.80(a)(2)
What is FDA's purpose for requiring reports?514.80(a)(3)
Do applicants of Type A medicated articles have to establish, maintain and report information required under § 514.80?514.80(a)(4)
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How do the requirements under § 514.80 relate to current good manufacturing practices?514.80(a)(5)
514.80(b) Reporting Requirements
What are the requirements for reporting product/manufacturing defects?514.80(b)(1) Three-day NADA/ANADA Field Alert Report
514.80(b)(2) Fifteen-day NADA/ANADA Alert Report
What are the requirements for reporting serious, unexpected and adverse drug experiences?514.80(b)(2)(i) Initial Report
What are the requirements for followup reporting of serious, unexpected adverse drug experiences?514.80(b)(2)(ii) Followup Report
What are the requirements for reporting increases in the frequency of serious, expected and unexpected, and adverse drug experiences?514.80(b)(2)(iii) Summary Report of Increased Frequency of Adverse Drug Experience
What are the requirements for nonapplicants for reporting adverse drug experiences?514.80(b)(3) Nonapplicant Report
What are the general requirements for submission of periodic drug experience reports, e.g., forms to be submitted, 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?514.80(b)(4) Periodic Drug Experience Reports
What must be submitted in the periodic drug experience reports?514.80(b)(4)(i) through (b)(4)(iv)
What distribution data must be submitted? How should the distribution data be submitted?514.80(b)(4)(i) Distribution Data
What labeling materials should be submitted? How do I report changes to the labeling materials since the last report?514.80(b)(4)(ii) Labeling
514.80(b)(4)(iii) Nonclinical Laboratory Studies and Clinical Data Not Previously Reported
What are the requirements for submission of nonclinical laboratory studies?514.80(b)(4)(iii)(A)
What are the requirements for submission of clinical laboratory data?514.80(b)(4)(iii)(B)
When must results of clinical trials conducted by or for the applicant be reported?514.80(b)(4)(iii)(C)
514.80(b)(4)(iv) Adverse Drug Experiences
How do I report product/manufacturing defects and adverse drug experiences not previously reported to FDA?514.80(b)(4)(iv)(A)
What are the requirements for submitting adverse drug experiences cited in literature?514.80(b)(4)(iv)(B)
What are the requirements for submitting adverse drug experiences in postapproval studies and clinical trials?514.80(b)(4)(iv)(C)
514.80(b)(5) Other Reporting
Can FDA request that an applicant submit information at different times than stated specifically in this regulation?514.80(b)(5)(i) Special Drug Experience Report
What are the requirements for submission of advertisement and promotional labeling to FDA?514.80(b)(5)(ii) Advertisements and Promotional Material
What are the requirements for adding a new distributor to the approved application?514.80(b)(5)(iii) Distributor's Statement
What labels and how many labels need to be submitted for review?514.80(b)(5)(iii)(A)
What changes are required and allowed to distributor labeling?514.80(b)(5)(iii)(A)(I)
What are the requirements for making other changes to the distributor labeling?514.80(b)(5)(iii)(A)(II)
What information should be included in each new distributor's signed statement?514.80(b)(5)(iii)(B)(I) through (B)(V)
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What are the conditions for submitting information that is common to more than one application? (i.e., can I submit common information to one application?)514.80(c) Multiple Applications
What information has to be submitted to the common application and related application?514.80(c)(1) through (c)(4)
What forms do I need? What are Forms FDA 1932 and 2301? How can I get them? Can I use computer-generated equivalents?514.80(d) Reporting Forms
How long must I maintain Form FDA 1932 and records and reports of other required information, i.e., how long do I need to maintain this information?514.80(e) Records to be Maintained
What are the requirements for allowing access to these records and reports, and copying by authorized FDA officer or employee?514.80(f) Access to Records and Reports
How do I obtain Forms FDA 1932 and 2301? Where do I mail FDA's required forms, records, and reports?514.80(g) Mailing Address
What happens if the applicant fails to establish, maintain, or make the required reports? What happens if the applicant refuses to allow FDA access to, and/or copying and/or verify records and reports?514.80(h) Withdrawal of Approval
Does an adverse drug experience reflect a conclusion that the report or information constitutes an admission that the drug caused an adverse effect?514.80(i) Disclaimer

(a) Applicability. (1) Each applicant and nonapplicant must establish and maintain indexed, separate, and complete files containing full records of all information pertinent to safety or effectiveness of a new animal drug that has not been previously submitted as part of the NADA or ANADA. Such records must include information from domestic, as well as foreign sources.

(2) Each applicant must submit reports of data, studies, and other information concerning experience with new animal drugs to the Food and Drug Administration (FDA) for each approved NADA and ANADA, as required in this section. A nonapplicant must submit data, studies, and other information concerning experience with new animal drugs to the appropriate applicant, as required in this section. The applicant, in turn, must report the nonapplicant's data, studies, and other information to FDA. Applicants and nonapplicants must submit data, studies, and other information described in this section from domestic, as well as foreign sources.

(3) FDA reviews the records and reports required in this section to facilitate a determination under section 512(e) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360b) as to whether there may be grounds for suspending or withdrawing approval of the NADA or ANADA.

(4) The requirements of this section also apply to any approved Type A medicated article. In addition, the requirements contained in § 514.80(b)(1), (b)(2), and (b)(4)(iv) apply to any approved Type A medicated article incorporated in animal feeds.

(5) The records and reports referred to in this section are in addition to those required by the current good manufacturing practice regulations in parts 211, 225, and 226 of this chapter.

(b) Reporting requirements—(1) Three-day NADA/ANADA field alert report. This report provides information pertaining to product and manufacturing defects that may result in serious adverse drug events. The applicant (or nonapplicant through the applicant) must submit the report to the appropriate FDA District Office or local FDA resident post within 3 working days of first becoming aware that a defect may exist. The information initially may be provided by telephone or other telecommunication means, with prompt written followup using Form FDA 1932 “Veterinary Adverse Drug Reaction, Lack of Effectiveness, Product Defect Report.” The mailing cover for these reports must be plainly marked “3-Day NADA/ANADA Field Alert Report.”

(2) Fifteen-day NADA/ANADA alert report—(i) Initial report. This report provides information on each serious, unexpected adverse drug event, regardless of the source of the information. The applicant (or nonapplicant through the applicant) must submit the report to FDA within 15 working days of first receiving the information. The report must be submitted on Form FDA 1932, and its mailing cover must be plainly marked “15-Day NADA/ANADA Alert Report.”

(ii) Followup report. The applicant must promptly investigate all adverse drug events that are the subject of 15-day NADA/ANADA alert reports. If this investigation reveals significant new information, a followup report must be submitted within 15 working days of receiving such information. A followup report must be submitted on Form FDA 1932, and its mailing cover must be plainly marked “15-Day NADA/ANADA Alert Report Followup.” The followup report must state the date of the initial report and provide the additional information. If additional information is sought but not obtained within 3 months of the initial report, a followup report is required describing the steps taken and why additional information was not obtained.

(iii) Summary report of increased frequency of adverse drug experience. The applicant must periodically review the incidence of reports of adverse drug experiences to determine if there has been an increased frequency of serious (expected and unexpected) adverse drug events. The applicant must report as soon as possible, but in any case within 15 working days of determining that there is an increased frequency of serious (expected and unexpected) adverse drug events. Summaries of reports of increased frequency of adverse drug events must be submitted in narrative form. The summaries must state the time period on which the increased frequency is based, time Start Printed Page 5060period comparisons in determining increased frequency, references to any previously submitted Form FDA 1932, the method of analysis, and the interpretation of the results. The summaries must be submitted under separate cover and may not be included, except for reference purposes, in a periodic drug experience report. The applicant must evaluate the increased frequency of serious (expected or unexpected) adverse drug events at least as often as reporting of periodic drug experience reports.

(3) Nonapplicant report. Nonapplicants must forward reports of adverse drug experiences to the applicant within 3 working days of first receiving the information. The applicant must then submit the report(s) to FDA as required in this section. The nonapplicant must maintain records of all nonapplicant reports, including the date the nonapplicant received the information concerning adverse drug experiences, the name and address of the applicant, and a copy of the adverse drug experience report including the date such report was submitted to the applicant. If the nonapplicant elects to also report directly to FDA, the nonapplicant should submit the report on Form FDA 1932 within 15 working days of first receiving the information.

(4) Periodic drug experience report. This report must be accompanied by a completed Form FDA 2301 “Transmittal of Periodic Reports and Promotional Materials for New Animal Drugs.” It must be submitted every 6 months for the first 2 years following approval of an NADA or ANADA and yearly thereafter. Reports required by this section must contain data and information for the full reporting period. The 6-month periodic drug experience reports must be submitted within 30 days following the end of the 6-month reporting period. The yearly periodic drug experience reports must be submitted within 60 days of the anniversary date of the approval of the NADA or ANADA. Any previously submitted information contained in the report must be identified as such. For yearly (annual) periodic drug experience reports, the applicant may petition FDA to change the date of submission or frequency of reporting, and after approval of such petition, file such reports on the new filing date or at the new reporting frequency. Also, FDA may require a report at different times or more frequently. The periodic drug experience report must contain the following:

(i) Distribution data. Information about the distribution of each new animal drug product, including information on any distributor-labeled product. This information must include the total number of distributed units of each size, strength, or potency (e.g., 100,000 bottles of 100 5-milligram tablets; 50,000 10-milliliter vials of 5 percent solution). This information must be presented in two categories: quantities distributed domestically and quantities exported.

(ii) Labeling. Applicant and distributor current package labeling, including package inserts (if any). For large-size package labeling or large shipping cartons, a representative copy must be submitted (e.g., a photocopy of pertinent areas of large feed bags). A summary of any changes in labeling made since the last report (listed by date of implementation) must be included with the labeling or if there have been no changes, a statement of such fact must be included with the labeling.

(iii) Nonclinical laboratory studies and clinical data not previously reported.

(A) Copies of in vitro studies (e.g., mutagenicity) and other nonclinical laboratory studies conducted by or otherwise obtained by the applicant.

(B) Copies of published clinical trials of the new animal drug (or abstracts of them) including clinical trials on safety and effectiveness, clinical trials on new uses, and reports of clinical experience pertinent to safety conducted by or otherwise obtained by the applicant. Review articles, papers, and abstracts in which the drug is used as a research tool, promotional articles, press clippings, and papers that do not contain tabulations or summaries of original data are not required to be reported.

(C) Descriptions of, or if available, prepublication manuscripts relating to completed clinical trials conducted by or otherwise known to the applicant. Supporting information is not to be reported. A study must be submitted no later than 1 year after completion of research.

(iv) Adverse drug experiences. (A) Product/manufacturing defects and adverse drug experiences not previously reported under § 514.80(b)(1) and (b)(2) must be reported individually on Form FDA 1932.

(B) Reports of adverse drug experiences in the literature must be noted in the periodic drug experience report. A bibliography of pertinent references must be included with the report. Upon FDA's request, the applicant must provide a full text copy of these publications.

(C) Reports of previously not reported adverse drug experiences that occur in postapproval studies must be reported separately from other experiences in the periodic drug experience report and clearly marked or highlighted.

(5) Other reporting—(i) Special drug experience report. Upon written request, FDA may require that the applicant submit a report required under § 514.80 at different times or more frequently than the timeframes stated in § 514.80.

(ii) Advertisements and promotional labeling. The applicant must submit at the time of initial dissemination one set of specimens of mailing pieces and other labeling for prescription and over-the-counter new animal drugs. For prescription new animal drugs, the applicant must also submit one set of specimens of any advertisement at the time of initial publication or broadcast. Mailing pieces and labeling designed to contain product samples must be complete except that product samples may be omitted. Each submission of promotional material must be accompanied by a completed Form FDA 2301.

(iii) Distributor's statement. At the time of initial distribution of a new animal drug product by a distributor, the applicant must submit a special drug experience report accompanied by a completed Form FDA 2301 containing the following:

(A) The distributor's current product labeling.

(1) The distributor's labeling must be identical to that in the approved NADA/ANADA except for a different and suitable proprietary name (if used) and the name and address of the distributor. The name and address of the distributor must be preceded by an appropriate qualifying phrase such as “manufactured for” or “distributed by.”

(2) Other labeling changes must be the subject of a supplemental NADA or ANADA as described under § 514.8.

(B) A signed statement by the distributor stating:

(1) The category of the distributor's operations (e.g., wholesale or retail),

(2) That the distributor will distribute the new animal drug only under the approved labeling,

(3) That the distributor will advertise the product only for use under the conditions stated in the approved labeling,

(4) That the distributor will adhere to the records and reports requirements of this section, and

(5) That the distributor is regularly and lawfully engaged in the distribution or dispensing of prescription products if the product is a prescription new animal drug.

(c) Multiple applications. Whenever an applicant is required to submit a periodic drug experience report under Start Printed Page 5061the provisions of § 514.80(b)(4) with respect to more than one approved NADA or ANADA for preparations containing the same new animal drug so that the same information is required to be reported for more than one application, the applicant may elect to submit as a part of the report for one such application (the primary application) all the information common to such applications in lieu of reporting separately and repetitively on each. If the applicant elects to do this, the applicant must do the following:

(1) State when a report applies to multiple applications and identify all related applications for which the report is submitted by NADA or ANADA number.

(2) Ensure that the primary application contains a list of the NADA or ANADA numbers of all related applications.

(3) Submit a completed Form FDA 2301 to the primary application and each related application with reference to the primary application by NADA/ANADA number and submission date for the complete report of the common information.

(4) All other information specific to a particular NADA/ANADA must be included in the report for that particular NADA/ANADA.

(d) Reporting forms. Applicant must report adverse drug experiences and product/manufacturing defects on Form FDA 1932, “Veterinary Adverse Drug Reaction, Lack of Effectiveness, Product Defect Report.” Periodic drug experience reports and special drug experience reports must be accompanied by a completed Form FDA 2301 “Transmittal of Periodic Reports and Promotional Material for New Animal Drugs,” in accordance with directions provided on the forms. Computer-generated equivalents of Form FDA 1932 or Form FDA 2301, approved by FDA prior to use, may be used. Form FDA 1932 and Form FDA 2301 may be obtained on the Internet at http://www.cvm.fda.gov/​cvm, by telephoning the Division of Surveillance (HFV-210), or by submitting a written request to the following address: Food and Drug Administration, Center for Veterinary Medicine, Division of Surveillance (HFV-210), 7500 Standish Pl., Rockville, MD 20855-2764.

(e) Records to be maintained. The applicants and nonapplicants must maintain records and reports of all information required by this section for a period of 5 years after the date of submission.

(f) Access to records and reports. The applicant and nonapplicant must, upon request from any authorized FDA officer or employee, at all reasonable times, permit such officer or employee to have access to copy and to verify all such required records and reports.

(g) Mailing addresses. Completed 15-day alert reports, periodic drug experience reports, and special drug experience reports must be submitted to the following address: Food and Drug Administration, Center for Veterinary Medicine, Document Control Unit (HFV-199), 7500 Standish Pl., Rockville, MD 20855-2764. Three-day alert reports must be submitted to the appropriate FDA district office or local FDA resident post. Addresses for district offices and resident posts may be obtained from the Internet at http://www.fda.gov.

(h) Withdrawal of approval. If FDA finds that the applicant has failed to establish the required records, or has failed to maintain those records, or failed to make the required reports, or has refused access to an authorized FDA officer or employee to copy or to verify such records or reports, FDA may withdraw approval of the application to which such records or reports relate. If FDA determines that withdrawal of the approval is necessary, the agency shall give the applicant notice and opportunity for hearing, as provided in § 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.

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Dated: January 21, 2002.

Margaret M. Dotzel,

Associate Commissioner for Policy.

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[FR Doc. 02-2549 Filed 2-1-02; 8:45 am]

BILLING CODE 4160-01-S