[Federal Register Volume 83, Number 96 (Thursday, May 17, 2018)]
[Rules and Regulations]
[Pages 22832-22836]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-10540]


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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: Final rule.

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SUMMARY: We are amending the Virus-Serum-Toxin Act regulations 
concerning records and reports. This change requires 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 (APHIS) will be provided in separate guidance 
documents. These records and reports will help ensure that APHIS can 
provide complete and accurate information to consumers regarding 
adverse reactions or other problems associated with the use of licensed 
biological products.

DATES: Effective June 18, 2018.

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.
    On September 4, 2015, we published in the Federal Register (80 FR 
53475-53478, Docket No. APHIS-2014-0063) a proposal \1\ to amend the 
regulations by establishing definitions for the terms adverse event and 
adverse event report and by providing requirements for adverse event 
records and reports. The changes we proposed are 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.
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    \1\ To view the proposed rule, supporting document, and the 
comments we received, go to http://www.regulations.gov/#!docketDetail;D=APHIS-2014-0063.
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    The purpose of VICH is to harmonize technical requirements for 
veterinary medicinal products (both pharmaceuticals and biologics). As 
a VICH member, the Animal and Plant Health Inspection Service (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: Pharmacovigilance: Data 
Elements for Submission of Adverse Events Reports specifically 
addresses the information that should be included when submitting 
adverse event reports.\2\
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    \2\ The VICH pharmacovigilance guidelines can be accessed at 
http://www.vichsec.org/guidelines/pharmacovigilance.html.
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    We solicited comments concerning our proposal for 60 days ending 
November 3, 2015. We received four comments by that date. They were 
from industry associations, a manufacturer of veterinary biologics, and 
a private citizen. The commenters were generally supportive of the 
proposed rule but asked some questions and raised some concerns about 
the provisions. These comments are discussed below by topic.

General Comments

    One commenter stated that the current system for detecting safety 
issues with products has historically worked well. The commenter did 
not believe there have been significant safety issues that have not 
been detected in a timely fashion.
    APHIS agrees with the commenter that the existing system has worked 
well. However, we believe that this rule will significantly improve the 
existing system by enhancing our ability to monitor the observed 
performance of veterinary biologics. For example, currently each 
veterinary biologics manufacturer makes an independent determination 
concerning whether an adverse event report raises questions regarding 
purity, safety, potency, efficacy, preparation, testing, or 
distribution, and when and in what manner such a report of the adverse 
event will be provided to APHIS. Thus, without explicit reporting 
requirements concerning adverse events, reports that may signal 
problems concerning the use of veterinary biological products may not 
all be submitted to APHIS or may not be submitted in a timely manner.

[[Page 22833]]

Another objective of this rule is to implement VICH guidelines 
pertaining to international standards specific for pharmacovigilance, 
which may enhance the ability of the biologics industry to export their 
products.
    One commenter noted that the only VICH guideline specifically 
referenced in the proposed rule is VICH GL42. The commenter stated that 
where the final rule, guidance documents, or APHIS practice touches 
upon the subject matter in the VICH guidelines, APHIS should look to 
all the VICH guidelines to harmonize definitions and practices to the 
furthest extent possible. The commenter specifically mentioned VICH 
GL24, Pharmacovigilance of Veterinary Medicinal Products: Management of 
Adverse Event Reports as one which APHIS should consider when 
establishing future regulations or guidelines.
    APHIS agrees that consistency with all relevant VICH guidelines is 
important. In the proposed rule, we referenced GL42 because we were 
proposing to add definitions to 9 CFR part 101 which are consistent 
with definitions found in this guideline. In future actions, however, 
we will reference all VICH guidelines regarding pharmacovigilance. We 
will also review all VICH guidelines associated with pharmacovigilance 
and consider them when developing future guidance documents, and will 
provide an opportunity for the industry to review and comment on any 
such documents.
    One commenter stated that this rule should not be implemented until 
APHIS has the capability to receive submissions electronically. The 
commenter further stated that in establishing this capability APHIS 
should utilize the VICH Guidelines for the Electronic Standards for 
Transfer of Data, and Data Elements for Submission of Adverse Event 
Reports (VICH GL42, 30, and 35).
    APHIS agrees on the importance of electronic submission and we will 
prioritize the development of an electronic submission portal. However 
we do not agree that this rule should not be implemented until we have 
the capacity to receive electronic submissions. As noted above by 
another commenter, the current system for detecting safety signals with 
products has historically worked well. APHIS has, and will continue to 
have, the capability to receive adverse event information by phone, 
fax, email, etc. It is important to implement this rule in order to 
clarify specific reporting requirements and to harmonize with 
international standards. Since we already receive adverse event 
reports, we do not believe it is necessary to wait for the development 
of an electronic submission portal.
    One commenter stated that the same adverse event may be reported 
separately by two or more parties, such as the veterinarian and animal 
owner. The commenter stated that APHIS should ensure that it has the 
capability to detect any duplicate reports.
    We agree with the commenter and will work to develop internal 
systems to detect duplicate reports.
    One commenter recommended that APHIS engage the industry in 
substantial discussion relative to the method and process it will use 
for signal detection and trend analysis and signal assessment and 
management. The commenter stated that government and industry have the 
same goal of marketing pure, potent, safe, and effective products and 
industry is open to maintaining a partnership in signal detection, 
trend analysis, and risk management.
    APHIS agrees with the commenter and will continue to engage with 
industry as future guidance is developed.
    One commenter asked for clarification of APHIS expectations on the 
maintenance of pharmacovigilance data and practices when a facility is 
inspected.
    Proposed Sec.  116.9(a) provides that records must be maintained 
for 3 years after the date that the adverse event report is received.
    One commenter asked for clarification on the aspects of the adverse 
event data that will be subject to the Freedom of Information Act 
(FOIA) and/or routinely made available on the APHIS website. The 
commenter stated that they expected that FOIA requests for this data 
will be received and that this data has tremendous potential for 
misuse. The commenter strongly suggested that if the data is made 
available on the APHIS website, information should also be provided 
about the limitations on interpreting the data.
    In general, if APHIS receives a FOIA request for publicly available 
information, we do not need to supply the information to the requester. 
Instead, we provide guidance on where the information is available and 
how often it is updated. If the FOIA request is for specific data that 
is not available publicly, then we are mandated to supply the 
information in its entirety without redaction. If it is information 
owned by a biologics manufacturer, then APHIS will send the FOIA 
request and responsive records to the manufacturer for review and 
redaction, if the responsive records contain confidential business 
information or trade secrets.
    Because the adverse event reports we receive are voluntary, APHIS 
has not yet made summary reports available to the public. We are aware 
that the number of adverse event reports received are a very small 
percentage of what is occurring in the field. After mandatory adverse 
event reporting is implemented, APHIS will make summary reports 
publicly available on the APHIS website. APHIS is working to determine 
the specifics on how often those reports are published and what 
explanatory information is included.
    Though we have not finalized a process to manage this data 
publicly, we do agree with the commenter about the limitations on 
interpreting the data when made public. For example, comparing products 
by the prevalence of adverse event cases reported can be misleading if 
one does not consider the number of animals exposed for each respective 
product. Prior to implementing the process for public disclosure of the 
data, we will explore the method that best serves all veterinary 
biologics stakeholders. Included in this will be the review and 
consideration of how the Food and Drug Administration handles their 
pharmacovigilance data.
    One commenter recommended that APHIS remove the adverse event 
reporting restrictions on the licenses for conditionally licensed 
products. The commenter also recommended that APHIS engage with State 
veterinarians and inform them that adverse events will be made public 
and that the industry should not be required by the State to provide 
additional reports.
    APHIS intends to engage with State veterinarians and other public 
groups to advise them of the availability of adverse event reports on 
the APHIS website. However, we will not remove adverse reporting 
restrictions on licenses because there may be specific issues 
associated with a product that require clarification on the license.
    One commenter noted that the definition of an adverse event for 
diagnostic products includes ``failure in product performance.'' The 
commenter stated that most customer reports of problems can either be 
traced to technical errors, or cannot be replicated with the product 
itself. The commenter further stated that unverified reports should not 
be the basis of adverse event reports to APHIS. The commenter stated 
that it is fairly straightforward to verify a problem with kit 
performance, and it seems appropriate that this be part of the 
determination that an adverse event has occurred.

[[Page 22834]]

    The commenter is correct that for diagnostic kits a ``failure in 
product performance'' refers to a verified failure of the product 
itself, and would not include reports associated with equipment failure 
or technical errors. We will clarify this in guidance documents.
    In the proposed rule, we estimated that each report would require 
0.33 hours to generate and submit. One commenter stated that this 
estimate is too low. The commenter stated that any formal communication 
with a regulatory agency requires fact-checking and review, which add 
to the time required to generate the report. The commenter stated that 
they believe that a minimum of two full-time equivalent hours would be 
required for a simple report, with 4 to 6 hours being a likely average 
for all reports.
    APHIS recognizes the variability in the time that it will take to 
gather, review, assess, and report adverse event cases to the agency. 
For example, the type of product (vaccine, diagnostic test kits, etc.) 
can have a significant influence in the respective time required to 
process a case. The reporting time would also vary depending on whether 
a licensee/permittee submits cases individually or batches multiple 
ones in a single submission. Therefore, considering the variability of 
processing adverse event reports for licensees/permittees, we would 
agree that a more accurate estimate of burden would be a range of 1 to 
3 hours.

Definitions

    One commenter stated that the proposed definition of adverse event 
should align with the definition in VICH GL24.
    VICH GL24, which refers to all veterinary medicinal products (VMP), 
defines an adverse event as ``any observation in animals, whether or 
not considered to be product-related, that is unfavorable and 
unintended and that occurs after any use of VMP (off-label and on-label 
uses). Included are events related to a suspected lack of expected 
efficacy according to approved labeling or noxious reactions in humans 
after being exposed to VMP(s).''
    We proposed to define an 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. APHIS believes that the two definitions are generally 
consistent and that the APHIS definition is appropriate for the 
regulation of veterinary biological products as compared to the 
regulation of all other veterinary medicinal products.
    One commenter stated that the definition of adverse event report in 
VICH GL24 requires a ``direct communication'' while the proposed APHIS 
definition referred to ``any communication.'' The commenter stated 
APHIS should use the words ``direct communication'' because this 
language would trigger reporting based upon reliable information; and 
specifically would not trigger reporting simply because the licensee 
became aware of, for example, an unsubstantiated blog post or 
anti[hyphen]product activity on the internet.
    APHIS agrees with the commenter. We have amended the definition of 
adverse event report to read ``direct communication'' instead of ``any 
communication''.
    One commenter noted that an adverse event report is defined as a 
communication received by a firm regarding an adverse event and which 
includes several pieces of information, including an ``identifiable 
animal.'' The commenter stated that test kits for diseases of livestock 
and poultry are most often used in laboratories, not at the location of 
the animals. The commenter further stated that laboratories would only 
rarely have access to individual animal identification devices in the 
normal course of their work. The commenter stated that if the intent of 
the rule is that all information listed must be available before a 
report to APHIS is required, that could greatly limit the number of 
reports. The commenter asked for clarification of the intent of the 
rule in this regard.
    APHIS agrees that this could be clearer. In cases where specific 
information regarding an animal identity is not readily available, we 
consider the species for which the product was used to be the minimum 
information for an ``identifiable animal.''

Frequency of Reporting

    One commenter noted that the terms serious adverse event and 
unexpected adverse event, which appear in VICH GL24, were not defined 
in the proposed rule. The commenter stated that those terms should not 
be considered factors that determine frequency of reporting.
    APHIS intends to define these terms in guidance documents that will 
be made available for review and comment by the industry and public 
before they are finalized. APHIS will work with the industry to develop 
guidance on these topics as the need arises.
    One commenter asked for clarification that APHIS is seeking 
spontaneous reports of adverse events, and not the results that could 
occur in clinical trials or other studies that would already be 
reported to APHIS in a study report, or adverse events that may be 
reported in the literature.
    The commenter is correct. Adverse event reports should address 
events that occur in field use of the product, not the results of 
clinical trials.
    One commenter stated that, in Sec.  116.9(b)(1), ``immediate'' 
should be interpreted to mean ``within 3 business days'' to be 
consistent with Veterinary Services Memorandum 800.57 ``Market 
Suspensions.'' The commenter stated that this would allow time for 
preliminary investigation. The commenter also stated that APHIS should 
replace the term ``immediate'' with ``3 business days'' in this 
section, as well as in Sec.  116.5(b).
    APHIS agrees that it is practical to interpret ``immediately'' as 
``within 3 business days'' and will clarify this in guidance documents, 
which will be needed to establish a consistent application to the 
interpretation of a serious event. The requirement in Sec.  116.9(b)(1) 
is consistent with the established requirement in Sec.  116.5(b), so we 
are making no changes to either paragraph.
    One commenter recommended that APHIS eliminate the 15 business day 
reporting requirement and any use of the concepts of 
``product[hyphen]related'', ``serious'', and ``expected'' for case 
management timelines. The commenter stated that even if these are 
eliminated, APHIS would still receive those adverse event reports that 
impact the purity, potency, safety, or efficacy of the product on a 3 
business day basis, and its ability to react very quickly to the most 
urgent situations would not be compromised. The commenter suggested 
that all other reports be submitted on the 90 calendar day requirement, 
which would provide sufficient time for a thorough investigation. A 
second commenter stated that a 90 day reporting period is too brief a 
period of time to submit reports; many of which will have nothing to 
report. The commenter suggested changes in the length of the reporting 
period over time
    APHIS agrees with the first commenter that serious and unexpected 
adverse events will be reported immediately within 3 business days and

[[Page 22835]]

as such the requirement of 15 business days is not necessary. We have 
amended Sec.  116.9(b)(2) to remove the 15 day reporting requirement. 
Adverse event reports will continue to be received immediately or 
within 90 calendar days. We have also amended Sec.  116.9(b) to require 
that adverse event reports determined to be product[hyphen]related, 
serious, and unexpected will be reported immediately and that other 
reports will be received within 90 days. We will also clarify that 
``immediately'' means ``within 3 business days'' in guidance documents. 
We do not agree with the second commenter regarding the need for the 90 
day reporting period, with changes in the length of the reporting 
period changing over time. Since we have removed the 15 day reporting 
period, the 90 day period will need to remain as a standard time. 
However, as pharmacovigilance data is accumulated APHIS will consider 
exemptions and will clarify in future guidance documents.
    Therefore, for the reasons given in the proposed rule and in this 
document, we are adopting the proposed rule as a final rule, with the 
changes discussed in this document.

Executive Orders 12866 and 13771 and Regulatory Flexibility Act

    This final 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. This rule is not an Executive 
Order 13771 regulatory action because this rule is not significant 
under Executive Order 12866.
    In accordance with 5 U.S.C. 604, we have performed a final 
regulatory flexibility analysis, which is summarized below, regarding 
the economic effects of this rule on small entities. Copies of the full 
analysis are available on the Regulations.gov website (see footnote 1 
in this document for a link to Regulations.gov) or by contacting the 
person listed under FOR FURTHER INFORMATION CONTACT.
    We are amending 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 type of information that must be included in 
the adverse event reports submitted to APHIS would be provided in 
separate guidance documents.
    We are taking this action in order to limit the harm to animals due 
to adverse events related to a product's purity, safety, potency, 
efficacy, preparation, testing, or distribution. Current regulations 
may hinder APHIS from taking expeditious action in cases where 
veterinary biologics are unsatisfactory.
    For animal owners, the monetary benefits of the proposal are 
difficult to estimate because they would depend on unknowable factors--
the significance or gravity of the harm that would be avoided with the 
rule in effect, and the number and value of animals thereby protected. 
Manufacturer costs to comply with the proposed rule are expected be 
minimal; most establishments that would be affected already maintain 
recordkeeping systems for adverse event reports that capture most if 
not all of the information that would be required. Most of the 
establishments that would be affected by the proposed rule are small 
entities.

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 final rule has been reviewed under Executive Order 12988, 
Civil Justice Reform. It is not intended to have retroactive effect. 
This rule will 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 final rule, which were 
filed under 0579-0209, have been submitted for approval to the Office 
of Management and Budget (OMB). When OMB notifies us of its decision, 
if approval is denied, we will publish a document in the Federal 
Register providing notice of what action we plan to take.

E-Government Act Compliance

    The Animal and Plant Health Inspection Service is committed to 
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 rule, please contact Ms. Kimberly Hardy, 
APHIS' Information Collection Coordinator, at (301) 851-2483.

Lists of Subjects

9 CFR Part 101

    Animal biologics.

9 CFR Part 116

    Animal biologics, Reporting and recordkeeping requirements.

    Accordingly, we are amending 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. Direct 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

[[Page 22836]]

    (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.

(Approved by the Office of Management and Budget under control 
number 0579-0013)

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 website at https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/veterinary-biologics or 
by writing to APHIS Center for Veterinary Biologics, 1920 Dayton 
Avenue, P.O. Box 844, Ames, Iowa 50010.
    (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 also be reported 
immediately.
    (3) All other adverse event reports must be reported within 90 
calendar days of the date the report was first received.

(Approved by the Office of Management and Budget under control 
number 0579-0209)

    Done in Washington, DC, this 11th day of May 2018.
 Kevin Shea,
Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 2018-10540 Filed 5-16-18; 8:45 am]
 BILLING CODE 3410-34-P