[Federal Register Volume 80, Number 172 (Friday, September 4, 2015)]
[Proposed Rules]
[Pages 53475-53478]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-21997]


 ========================================================================
 Proposed Rules
                                                 Federal Register
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 This section of the FEDERAL REGISTER contains notices to the public of 
 the proposed issuance of rules and regulations. The purpose of these 
 notices is to give interested persons an opportunity to participate in 
 the rule making prior to the adoption of the final rules.
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  Federal Register / Vol. 80, No. 172 / Friday, September 4, 2015 / 
Proposed Rules  

[[Page 53475]]



DEPARTMENT OF AGRICULTURE

Animal and Plant Health Inspection Service

9 CFR Parts 101 and 116

[Docket No. APHIS-2014-0063]
RIN 0579-AE11


VSTA Records and Reports Specific to International Standards for 
Pharmacovigilance

AGENCY: Animal and Plant Health Inspection Service, USDA.

ACTION: Proposed rule; withdrawal and reproposal.

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SUMMARY: We are proposing to amend the Virus-Serum-Toxin Act 
regulations concerning records and reports. This change would require 
veterinary biologics licensees and permittees to record and submit 
reports concerning adverse events associated with the use of biological 
products they produce or distribute. The information that must be 
included in the adverse event reports submitted to the Animal and Plant 
Health Inspection Service would be provided in separate guidance 
documents. This proposed rule replaces a previously published proposed 
rule, which we are withdrawing as part of this document.

DATES: We will consider all comments that we receive on or before 
November 3, 2015.

ADDRESSES: You may submit comments by either of the following methods:
     Federal eRulemaking Portal: Go to http://www.regulations.gov/#!docketDetail;D=APHIS-2014-0063.
     Postal Mail/Commercial Delivery: Send your comment to 
Docket No. APHIS-2014-0063, Regulatory Analysis and Development, PPD, 
APHIS, Station 3A-03.8, 4700 River Road Unit 118, Riverdale, MD 20737-
1238.
    Supporting documents and any comments we receive on this docket may 
be viewed at http://www.regulations.gov/#!docketDetail;D=APHIS-2014-
0063 or in our reading Room, which is located in Room 1141 of the USDA 
South Building, 14th Street and Independence Avenue SW., Washington, 
DC. Normal reading room hours are 8 a.m. to 4:30 p.m., Monday through 
Friday, except holidays. To be sure someone is there to help you, 
please call (202) 799-7039 before coming.

FOR FURTHER INFORMATION CONTACT: Dr. Donna L. Malloy, Section Leader, 
Operational Support, Center for Veterinary Biologics Policy, 
Evaluation, and Licensing, VS, APHIS, 4700 River Road Unit 148, 
Riverdale, MD 20737-1231; (301) 851-3426.

SUPPLEMENTARY INFORMATION:

Background

    The Virus-Serum-Toxin Act regulations in 9 CFR part 116 (referred 
to below as the regulations) contain requirements for maintaining 
detailed records of information necessary to give a complete accounting 
of all the activities within a veterinary biologics establishment. 
These records include records and reports for unfavorable or unintended 
events that occur in animals after the use of a biological product.
    Specifically, the regulations in Sec.  116.1, paragraph (a) state 
that such reports must include, but are not limited to, the items 
enumerated in the regulations, including inventory and disposition 
records, (Sec.  116.2), information concerning product development and 
preparation and market suspension and recalls (Sec.  116.5), animal 
records (Sec.  116.6), and test records (Sec.  116.7).
    In Sec.  116.5, paragraph (b) states that if at any time there are 
indications that raise questions regarding the purity, safety, potency, 
or efficacy of a product, or if it appears that there may be a problem 
regarding the preparation, testing, or distribution of a product, the 
licensee, permittee, or foreign manufacturer must immediately notify 
the Animal and Plant Health Inspection Service (APHIS) concerning the 
circumstances and the action taken, if any.
    However, the regulations in Sec.  116.1 do not explicitly require 
licensees and permittees to maintain records of adverse events 
associated with the use of veterinary biologics, nor do the regulations 
in Sec.  116.5 provide specific guidance in determining whether an 
adverse event should be considered an indication that raises questions 
regarding the purity, safety, potency, efficacy, preparation, testing, 
or distribution (PSPEPTD) of such product. Consequently, each 
veterinary biologics manufacturer makes an independent determination 
concerning (1) whether an adverse event report raises PSPEPTD questions 
and (2) when and in what manner such report of the adverse event will 
be provided to APHIS.
    To limit the harm to animals posed by unsatisfactory veterinary 
biologics, APHIS must rely on adverse event reports provided by 
veterinary biologics licensees and permittees. However, without any 
explicit guidance as to the form those reports should take, licensees 
and permittees are using nonstandardized methods to record and submit 
reports regarding adverse events to APHIS. Similarly, without explicit 
reporting requirements concerning adverse events, reports that may 
signal problems concerning the use of veterinary biological products 
are not all being submitted to APHIS in a timely manner.
    The changes we are proposing are also consistent with guidelines 
set out by the International Cooperation on Harmonization of Technical 
Requirements for Registration of Veterinary Medicinal Products (VICH). 
VICH is a unique project conducted under the World Organization for 
Animal Health, that brings together the regulatory authorities of the 
European Union, Japan, and the United States and representatives from 
the animal health industry in the three regions. Regulatory authorities 
and industry experts from Australia, Canada, and New Zealand 
participate as observers.
    The purpose of VICH is to harmonize technical requirements for 
veterinary medicinal products (both pharmaceuticals and biologics). As 
a VICH member, APHIS provides expertise on veterinary biological 
products and participates in efforts to enhance harmonization. Both 
APHIS and the animal health industry are committed to seek 
scientifically based harmonized technical requirements for the 
development and use of veterinary biological products. VICH Guideline 
GL42 specifically addresses data

[[Page 53476]]

elements for submission of adverse event reports.\1\
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    \1\ The VICH pharmacovigilance guidelines can be accessed at 
http://www.vichsec.org/guidelines/pharmacovigilance.html.
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    By amending our regulations based on VICH pharmacovigilance 
guidelines we would be integrating into our regulations internationally 
accepted practices that would enhance the safety and efficacy of 
veterinary biologics in the United States. Furthermore, our consistency 
with these international guidelines would enhance the ability of the 
U.S. biologics industry to export their products.
    We have previously undertaken rulemaking to address the problems 
described above and to bring our reporting and recordkeeping 
requirements into closer alignment with the VICH guidelines. 
Specifically, on August 17, 2005, we published in the Federal Register 
(70 FR 48325-48329, Docket No. 00-071-2) a proposed rule \2\ to amend 
the regulations concerning records and reports to require veterinary 
biologics licensees and permittees to record and submit reports to 
APHIS concerning adverse events associated with the use of veterinary 
biological products that they produce or distribute. The proposed rule 
would have required veterinary biologics licensees and permittees to 
report to APHIS the number of doses of each licensed product that they 
distribute. The proposed rule also would have amended the regulations 
in 9 CFR part 101 to provide definitions for the terms adverse event 
and adverse event report.
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    \2\ To view the proposed rule and the comments we received, go 
to http://www.regulations.gov/#!docketDetail;D=APHIS-2005-0071.
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    We solicited comments on our proposal for 60 days ending on October 
17, 2005. We received seven comments by that date. The comments were 
from industry associations, manufacturers of veterinary biologics, and 
a software company that specializes in pharmacovigilance. Four of these 
commenters expressed conceptual support for the proposed rule, but were 
concerned that parts of the proposed regulations were overly broad or 
ambiguous and would increase the regulatory burden on the industry and 
possibly compromise confidential business information. One commenter 
was skeptical of the need for the rule. The remaining commenters 
neither supported nor opposed the rule but instead either asked for 
clarification or suggested wording that they believed would provide 
greater clarity.
    In response to these comments, we believe it is necessary to 
clarify those provisions that could be subject to multiple 
interpretations and to provide more specifics concerning the 
information that should be included in adverse event reports associated 
with the use of veterinary biologics that are submitted to the Agency. 
Therefore, we are withdrawing the August 17, 2005, proposed rule and 
are replacing it with the proposed changes described in this document. 
The proposed recordkeeping and reporting requirements regarding adverse 
events that would apply to each licensee, permittee, and foreign 
establishment that prepares and distributes biological products are 
described below.

Definitions

    The regulations in 9 CFR part 101 contain definitions of terms used 
in the regulations concerning veterinary biologics. The proposed 
changes to part 116 of the regulations would make it necessary for us 
to add definitions for two terms used in the proposed regulations to 
Sec.  101.2. We would define adverse event as ``any observation in 
animals, whether or not the cause of the event is known, that is 
unfavorable and unintended, and that occurs after any use (as indicated 
on the label or any off-label use) of a biological product, including 
events related to a suspected lack of expected efficacy. For products 
intended to diagnose disease, adverse events refer to a failure in 
product performance that hinders an expected discovery of the correct 
diagnosis.'' We would define adverse event report as ``any 
communication concerning the occurrence of an adverse event from an 
identifiable first-hand reporter which includes at least the following 
information: An identifiable reporter; an identifiable animal; an 
identifiable biologic product; and one or more adverse events.''

Adverse Event Records

    We are proposing to add a new Sec.  116.9 to provide requirements 
for adverse event records and reports. First, we would require that 
licensees and permittees maintain a detailed record for every adverse 
event report the licensee or permittee receives that is associated with 
the use of biological products they produce or distribute. APHIS will 
provide guidance on the information to be included in the reports on 
our Web site, based on the recommendations in the VICH Guideline GL42, 
which addresses data elements for submission of adverse event reports. 
We will release guidance documents as a final rule is being 
implemented, and we will make the documents available on our Web site 
in draft form for public comment.
    Second, we would require that licensees and permittees compile a 
report of all adverse events reports they receive and submit that 
report to the APHIS at regular intervals. Specifically, we would 
require that these reports be submitted immediately if at any time 
there are indications that raise questions regarding the purity, 
safety, potency, or efficacy of a product, or if it appears that there 
may be a problem regarding the preparation, testing, or distribution of 
a product. If the licensee or permittee determines the adverse event 
report to be product-related, serious, and unexpected, the report would 
have to be submitted to APHIS within 15 business days of the date the 
report was first received. All other adverse event reports would have 
to be submitted within 90 calendar days of the date the report was 
first received.

Completion of Records

    The regulations in Sec. Sec.  116.1(a)(3) and 116.8 provide that 
all records (other than disposition records) required under part 116 
shall be completed by the licensee, permittee, or foreign manufacturer 
before any portion of a serial of any product may be marketed in the 
United States or exported. We are proposing to amend those provisions 
to also allow adverse event records to be excluded from the list of 
records that must be completed before a product may be marketed or 
exported. Like disposition records, adverse event records could not be 
expected to have been completed prior to the marketing or exportation 
of a product.
    If this proposed rule is adopted as a final rule, there would be an 
18-month implementation period to allow licensees and permittees 
sufficient time to bring their recordkeeping and reporting into 
compliance with the new reporting and recordkeeping requirements.

Miscellaneous

    We would also make several minor, nonsubstantive changes to the 
regulations to improve their clarity.

Executive Order 12866 and Regulatory Flexibility Act

    This proposed rule has been determined to be not significant for 
the purposes of Executive Order 12866 and, therefore, has not been 
reviewed by the Office of Management and Budget.
    In accordance with 5 U.S.C. 603, we have performed an initial 
regulatory flexibility analysis, which is summarized below, regarding 
the economic effects of this rule on small entities. The full analysis 
may be viewed on the Regulations.gov Web site

[[Page 53477]]

(see ADDRESSES above for instructions for accessing Regulations.gov) or 
obtained from the person listed under FOR FURTHER INFORMATION CONTACT.
    The proposed rule would affect all of the approximately 314 U.S. 
veterinary biologics manufacturers, including permittees. All the 
affected entities would have to take at least some additional action--
even if that additional action involved sending a negative affirmation 
report to APHIS annually.
    The Small Business Administration (SBA) standard for establishments 
primarily engaged in manufacturing vaccines, toxoids, blood fractions, 
and culture media of plant or animal origin (NAICS 325414) is 500 
employees or fewer. It is reasonable to assume that most are small in 
size, under the SBA standards. This assumption is based on composite 
data for providers of the same and similar services in the United 
States. In 2012, there were 314 U.S. establishments in NAICS 325414 \3\ 
with a total employment of 40,411. The average number of employees per 
firm in 2012 was 128. Similarly, in 2012, there were 235 U.S. 
establishments in NAICS 325413, a classification comprised of 
establishments primarily engaged in manufacturing in-vitro diagnostic 
substances, including biological substances. The average number of 
employees per firm in 2012 was 108.\4\
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    \3\ http://thedataweb.rm.census.gov/TheDataWeb_HotReport2/econsnapshot/2012/snapshot.hrml?NAICS=325414.
    \4\ http://thedataweb.rm.census.gov/TheDataWeb_HotReport2/econsnapshot/2012/snapshot.hrml?NAICS=325413.
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    The proposed rule has the potential to benefit animals and their 
owners, to the extent that it allows APHIS to act quickly to limit the 
harm to animals posed by unsatisfactory veterinary biologics. For 
animal owners, the monetary benefits are difficult to estimate, because 
they would depend on several factors that are currently unknown--the 
significance, or gravity, of the harm that would be avoided with the 
rule in effect, and the number, and value, of animals that would avoid 
harm with the rule in effect. For some animal owners, especially those 
with large numbers of high value animals, the potential monetary 
benefits could be significant. This proposed rule clarifies reporting 
requirements. Manufacturer costs to comply with the proposed rule are 
expected be minimal in most cases. By revising our regulations based on 
VICH pharmacovigilance guidelines we will be applying an international 
standard to the industry which will enhance the safety and efficacy of 
veterinary biologics in the United States. Furthermore, our compliance 
with this international standard will enhance the ability of the 
biologics industry to export their products.

Executive Order 12372

    This program/activity is listed in the Catalog of Federal Domestic 
Assistance under No. 10.025 and is subject to Executive Order 12372, 
which requires intergovernmental consultation with State and local 
officials. (See 2 CFR chapter IV.)

Executive Order 12988

    This proposed rule has been reviewed under Executive Order 12988, 
Civil Justice Reform. It is not intended to have retroactive effect. 
This rule would not preempt any State or local laws, regulations, or 
policies where they are necessary to address local disease conditions 
or eradication programs. However, where safety, efficacy, purity, and 
potency of biological products are concerned, it is the Agency's intent 
to occupy the field. This includes, but is not limited to, the 
regulation of labeling. Under the Act, Congress clearly intended that 
there be national uniformity in the regulation of these products. There 
are no administrative proceedings which must be exhausted prior to a 
judicial challenge to the regulations under this rule.

Executive Order 13175

    This rule does not significantly or uniquely affect the communities 
of Indian tribal governments. The rule does not impose any mandate on 
tribal governments or impose any duties on these entities. Thus, no 
further action is required under Executive Order 13175.

Paperwork Reduction Act

    In accordance with section 3507(d) of the Paperwork Reduction Act 
of 1995 (44 U.S.C. 3501 et seq.), the information collection or 
recordkeeping requirements included in this proposed rule have been 
submitted for approval to the Office of Management and Budget (OMB). 
Please send written comments to the Office of Information and 
Regulatory Affairs, OMB, Attention: Desk Officer for APHIS, Washington, 
DC 20503. Please state that your comments refer to Docket No. APHIS-
2014-0063. Please send a copy of your comments to: (1) APHIS, using one 
of the methods described under ADDRESSES at the beginning of this 
document, and (2) Clearance Officer, OCIO, USDA, Room 404-W, 14th 
Street and Independence Avenue SW., Washington, DC 20250.
    This proposed rule would require veterinary biologics licensees and 
permittees to record and submit reports to APHIS concerning adverse 
events associated with the use of biological products they produce or 
distribute. APHIS would provide guidance as to the information to be 
included in these reports. The reports would also be required to be 
maintained for a specified amount of time.
    We are soliciting comments from the public (as well as affected 
agencies) concerning our proposed information collection and 
recordkeeping requirements. These comments will help us:
    (1) Evaluate whether the proposed information collection is 
necessary for the proper performance of our agency's functions, 
including whether the information will have practical utility;
    (2) Evaluate the accuracy of our estimate of the burden of the 
proposed information collection, including the validity of the 
methodology and assumptions used;
    (3) Enhance the quality, utility, and clarity of the information to 
be collected; and
    (4) Minimize the burden of the information collection on those who 
are to respond (such as through the use of appropriate automated, 
electronic, mechanical, or other technological collection techniques or 
other forms of information technology; e.g., permitting electronic 
submission of responses).
    Estimate of burden: Public reporting burden for this collection of 
information is estimated to average 0.33 hours per response.
    Respondents: U.S. importers and exporters of veterinary biological 
products, shippers of veterinary biological products, State veterinary 
authorities, and operators of establishments that produce or test 
veterinary biological products or that engage in product research and 
development.
    Estimated annual number of respondents: 9,999.
    Estimated annual number of responses per respondent: 1.59.
    Estimated annual number of responses: 15,996.
    Estimated total annual burden on respondents: 5,280 hours. (Due to 
averaging, the total annual burden hours may not equal the product of 
the annual number of responses multiplied by the reporting burden per 
response.)
    Copies of this information collection can be obtained from Ms. 
Kimberly Hardy, APHIS' Information Collection Coordinator, at (301) 
851-2727.

E-Government Act Compliance

    The Animal and Plant Health Inspection Service is committed to

[[Page 53478]]

compliance with the E-Government Act to promote the use of the Internet 
and other information technologies, to provide increased opportunities 
for citizen access to Government information and services, and for 
other purposes. For information pertinent to E-Government Act 
compliance related to this proposed rule, please contact Ms. Kimberly 
Hardy, APHIS' Information Collection Coordinator, at (301) 851-2727.

Lists of Subjects

9 CFR Part 101

    Animal biologics.

9 CFR Part 116

    Animal biologics, Reporting and recordkeeping requirements.

    Accordingly, we propose to amend 9 CFR parts 101 and 116 as 
follows:

PART 101--DEFINITIONS

0
1. The authority citation for part 101 continues to read as follows:

    Authority: 21 U.S.C. 151-159; 7 CFR 2.22, 2.80, and 371.4.

0
2. Section 101.2 is amended by adding definitions for adverse event and 
adverse event report in alphabetical order to read as follows:


Sec.  101.2  Administrative terminology.

* * * * *
    Adverse event. Any observation in animals, whether or not the cause 
of the event is known, that is unfavorable and unintended, and that 
occurs after any use (as indicated on the label or any off-label use) 
of a biological product, including events related to a suspected lack 
of expected efficacy. For products intended to diagnose disease, 
adverse events refer to a failure in product performance that hinders 
an expected discovery of the correct diagnosis.
    Adverse event report. Any communication concerning the occurrence 
of an adverse event from an identifiable first-hand reporter which 
includes the following information:
    (1) An identifiable reporter;
    (2) An identifiable animal;
    (3) An identifiable biologic product; and
    (4) One or more adverse events.
* * * * *

PART 116--RECORDS AND REPORTS

0
3. The authority citation for part 116 continues to read as follows:

    Authority:  21 U.S.C. 151-159; 7 CFR 2.22, 2.80, and 371.4.

0
4. In Sec.  116.1, paragraph (a)(3) is revised to read as follows:


Sec.  116.1  Applicability and general considerations.

    (a) * * *
    (3) Records (other than disposition records and adverse event 
records) required by this part must be completed by the licensee, 
permittee, or foreign manufacturer, as the case may be, before any 
portion of a serial of any product may be marketed in the United States 
or exported.
* * * * *
0
5. Section 116.8 is revised to read as follows:


Sec.  116.8  Completion and retention of records.

    All records (other than disposition records and adverse event 
records) required by this part must be completed by the licensee, 
permittee, or foreign manufacturer before any portion of a serial of 
any product may be marketed in the United States or exported. All 
records must be retained at the licensed or foreign establishment or 
permittee's place of business for a period of 2 years after the 
expiration date of a product or longer as may be required by the 
Administrator.
0
6. Section 116.9 is added to read as follows:


Sec.  116.9  Recording and reporting adverse events.

    (a) Licensees and permittees must maintain a detailed record for 
every adverse event report the licensee or permittee receives for any 
biological product it produces or distributes. These records shall be 
maintained for a period of 3 years after the date the adverse event 
report is received. The adverse event report form and guidance on how 
to complete it, including guidance specific to the various information 
blocks on the form, is available on the APHIS Web site at [ADDRESS TO 
BE ADDED IN FINAL RULE] or by writing to APHIS at [POSTAL ADDRESS TO BE 
ADDED IN FINAL RULE].
    (b) A report of all adverse events reports received by a licensee 
or permittee must be compiled and submitted to the Animal and Plant 
Health Inspection Service. The frequency of report submission is as 
follows:
    (1) Immediate notification is required if at any time there are 
indications that raise questions regarding the purity, safety, potency, 
or efficacy of a product, or if it appears that there may be a problem 
regarding the preparation, testing, or distribution of a product.
    (2) Adverse event reports determined by the licensee or permittee 
to be product-related, serious, and unexpected must be reported within 
15 business days of the date the report was first received.
    (3) All other adverse event reports must be reported within 90 
calendar days of the date the report was first received.

    Done in Washington, DC, this 31st day of August 2015.
Kevin Shea,
Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 2015-21997 Filed 9-3-15; 8:45 am]
 BILLING CODE 3410-34-P