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[Federal Register Volume 79, Number 76 (Monday, April 21, 2014)]
[Proposed Rules]
[Pages 22048-22051]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-08995]

========================================================================
Proposed Rules
                                                Federal Register
________________________________________________________________________

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.

========================================================================


Federal Register / Vol. 79, No. 76 / Monday, April 21, 2014 / 
Proposed Rules

[[Page 22048]]

DEPARTMENT OF AGRICULTURE

Animal and Plant Health Inspection Service

9 CFR Part 112

[Docket No. APHIS-2011-0049]
RIN 0579-AD64

Viruses, Serums, Toxins, and Analogous Products; Single Label 
Claim for Veterinary Biological Products

AGENCY: Animal and Plant Health Inspection Service, USDA.

ACTION: Proposed rule.

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

SUMMARY: We are proposing to amend the Virus-Serum-Toxin Act 
regulations to provide for the use of a simpler labeling format that 
would better communicate product performance to the user. We intend to 
replace the current label format, which reflects any of four different 
levels of effectiveness, with a single, uniform label format. We are 
also proposing to require biologics licensees to provide a standardized 
summary, with confidential business information removed, of the 
efficacy and safety data submitted to the Animal and Plant Health 
Inspection Service in support of the issuance of a full product license 
or conditional license. A simpler label format along with publicly 
available safety and efficacy data will help biologics producers to 
more clearly communicate product performance to their customers.

DATES: We will consider all comments that we receive on or before June 
20, 2014.

ADDRESSES: You may submit comments by either of the following methods:
     Federal eRulemaking Portal: Go to http://www.regulations.gov/#!documentDetail;D=APHIS-2011-0049-0009.
     Postal Mail/Commercial Delivery: Send your comment to 
Docket No. APHIS-2011-0049, 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-2011-
0049 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 Malloy, Operational Support 
Section, 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 Animal and Plant Health Inspection Service (APHIS) administers 
and enforces the Virus-Serum-Toxin Act, as amended (21 U.S.C. 151-159). 
The regulations issued pursuant to the Act are intended to ensure that 
veterinary biological products are pure, safe, potent, and efficacious 
when used according to label instruction. The regulations in 9 CFR part 
112, ``Packaging and Labeling,'' (referred to below as the regulations) 
prescribe requirements for the packaging and labeling of veterinary 
biologics. The regulations ensure that labeling provides adequate 
information concerning the proper use and safety of the product, 
including vaccination schedules, warnings, and cautions.
    Current APHIS guidelines provide examples of label claims that may 
be used to reflect the expected performance of the product provided 
that appropriate efficacy data has been submitted and approved by 
APHIS. The guidelines describe performance requirements and allowable 
indications statements for four different levels (tiers) of 
effectiveness.
    In July 2009, representatives of veterinary biologics manufacturers 
and the American Veterinary Medical Association (AVMA) met with APHIS 
to discuss the Agency's current labeling guidance and to explore the 
possibility of developing a single indications statement that would 
convey clinically useful information to veterinary practitioners and 
other consumers of veterinary biologics. At that meeting, the AVMA, 
which represents the largest group of consumers of veterinary 
biologics, informed APHIS that its members consider labeling 
indications statements based on the current guidance to be confusing, 
and expressed a desire for indications statements to provide insight 
into the actual performance of the product, including summaries of 
safety and efficacy data.
    On the other hand, representatives of the trade associations 
representing veterinary biologics manufacturers have remarked that 
their members expend significant resources on studies to provide data 
to support labeling that includes indications statements emphasizing 
the unique properties of their product versus that of a competitor. 
They expressed concern about any change to the labeling regulations 
that would de-emphasize product differences or require public 
disclosure of proprietary information that could compromise a 
manufacturer's competitive position in the marketplace.
    In response to the concerns expressed by these stakeholders, APHIS 
developed a draft guideline (concept paper) concerning the 
effectiveness indications statements used in veterinary biologics 
labeling. The draft guideline would replace current indications 
statements that may reflect any of four different levels of 
effectiveness with a single indications statement (e.g., a label claim 
stating that the product can be used ``as an aid in the prevention of 
------,'' ``as an aid in the control of ------,'' ``for the prevention 
of infection with ------,'' or ``for the prevention of disease due to 
------'' would be replaced with the statement ``This product has been 
shown to be effective for the vaccination of healthy animals ------
weeks of age or older against ------'').
    In addition to a standardized indications statement, the draft 
guideline would also require biologics licensees to provide a summary 
of their data, with confidential business information removed, of the 
efficacy and safety data submitted to APHIS in support of the issuance 
of the product license. These proposed changes would not alter the 
current efficacy requirements for veterinary biological products and 
are not intended to

[[Page 22049]]

constitute re-licensure of currently licensed products. These changes 
would not apply to diagnostic products.
    On May 24, 2011, we published in the Federal Register (76 FR 30093-
30094, Docket No. APHIS-2011-0049) a notice of a public meeting to 
discuss the draft guideline (concept paper) concerning effectiveness 
indications statements in veterinary biologics labeling. At the 
meeting, we received comments from national trade associations 
representing veterinary biologics manufacturers, the AVMA, a veterinary 
consulting group, private and academic veterinarians, pet owners, and 
manufacturers. There was general support to change the format in which 
expectations of product efficacy are communicated on labels. APHIS has 
carefully considered the comments received on the draft guideline and 
has taken these comments into account in the drafting of this proposed 
rule.
    Currently licensed products would not need to be re-licensed based 
on these proposed changes. This proposal is not intended to change the 
efficacy requirements for currently licensed veterinary biological 
products. Disease syndromes and primary parameters used in the case 
definitions would continue to be included in the indications statement 
where appropriate.
    The licensees would be required to provide the same data as is 
currently required under 9 CFR part 102. Summaries of these data will 
be made available to the public on the APHIS Center for Veterinary 
Biologics (CVB) Web site. We believe that providing safety and efficacy 
data combined with a simpler labeling format will allow the end user to 
better assess product performance.
    For the purposes of marketing, promotion, or advertising, the 
manufacturers could include a statement on promotional and advertising 
materials referring the user to the CVB Web site where additional 
efficacy and safety data may be found. Promotional studies would not be 
disclosed on the CVB Web site. We believe this is consistent with 
previous guidelines and regulations and would not confer an advantage 
to any particular manufacturer.
    The CVB Web site would also provide educational information to 
address the complex nature of efficacy studies as well as explanatory 
statistical information, where appropriate, related to individual data 
summaries. In addition, the Web site would include a statement advising 
users to consult with a licensed veterinarian for further information 
regarding the use of a veterinary biological product. We believe an 
educational component is an integral part of disseminating such complex 
information as efficacy and safety data.
    Biologics licensees would be responsible for providing data 
summaries with confidential business information removed. The licensee 
would be required to submit a summary of data with the efficacy/safety 
reports. If after reviewing the summary of data APHIS disagrees with 
the accompanying conclusions, APHIS would revise the summary and 
provide the licensee with the opportunity to review and comment on the 
revised summary prior to it being posted on the CVB Web site.
    The original efficacy and safety data for each component antigen in 
a product would remain on the Web site indefinitely. Post-licensure 
data supporting additional efficacy/safety claims, or changes in the 
time immunity is demonstrated (i.e., time interval between vaccination 
and challenge) would also be posted to the Web site alongside the 
original data summary. We believe that providing post-licensure 
efficacy and safety data alongside the original efficacy data would 
allow the end user to determine whether the manufacturer is 
maintaining, increasing, or decreasing the standards used to originally 
license the product.
    Several commenters requested information regarding how study design 
and results would be disclosed on the data summaries. Given the large 
number of diseases, vaccine types, and efficacy models, it is not 
possible to standardize the study design for all efficacy studies. 
Efficacy data summaries would include information regarding study 
design and associated raw data used to license the product. Parameters 
associated with study design would include: Minimum and maximum age of 
the target species; the diversity of target species; number of animals; 
whether animals were client owned; States where the study was 
conducted; serologic status of animals (including presence or absence 
of maternal antibody when appropriate); and dosage, timing, and route 
of administration. Information regarding the challenge organism would 
include the name of the organism (not strain) and concentration, time 
of challenge relative to the last vaccination, and whether the 
challenge organism is homologous or heterologous to the vaccine. Safety 
data summaries would include the same study design information as 
provided in efficacy data summaries and would include all adverse 
events that were observed throughout the course of the study.
    The primary outcome and clinically relevant outcomes of the study 
used for acceptance of the data by APHIS would have to be provided. The 
data summary would include neither case definitions nor statistical 
results of an inferential nature (e.g., confidence intervals and p-
values). The data would be sufficient to be reasonably understood by an 
individual with basic medical and scientific background yet contain 
sufficient information to allow a veterinarian to make an informed 
decision regarding the performance of the product(s). If the clinical 
sign is quantified rather than defined as either present or absent, the 
summary would provide sufficient information so the distribution of the 
responses could be understood. For example, in addition to the number 
of control and vaccinated animals with lung lesions, the summary could 
include such information as minimum, 25th percentile, median, 75th 
percentile, and maximum percent lung lesions for each group. We believe 
that presentation of efficacy and safety information as outlined above 
would appropriately reflect product performance in a standardized 
format without disclosing study information that may be confidential 
business information.
    After demonstrating the efficacy for a product that contains a 
combination of many antigens, the manufacturer often mixes those 
antigens into smaller combinations. Smaller combinations can then be 
licensed as fall-out products. With regard to the presentation of data 
for large combination products with fall-out products, in general, 
efficacy and safety studies are conducted on the largest combination 
product and not on fall-out products. Efficacy would have to be 
established for each component antigen in the largest combination 
product. Safety data summaries would have to be provided for the 
largest combination product. Efficacy data summaries would be posted 
for each component antigen on the large combination (parent) product 
with a list of all smaller fall-out products. Similarly, each fall-out 
product from a larger combination product would have to reference the 
parent product under which the efficacy data summary may be found. An 
educational component would be included on the efficacy and safety data 
summaries clarifying that fall-out products have been licensed based on 
efficacy and safety data of a larger combination product. We believe 
this would bridge data from larger combination products to their 
associated fall-out products. In order to provide a manageable workload 
for both the manufacturers and CVB, we will

[[Page 22050]]

provide manufacturers with the opportunity to prioritize the submission 
of product families.
    Products that are not yet licensed but are within 6 months of 
licensure at the time these proposed regulations may become effective 
would be expected to be fully compliant no later than 1 year after 
licensure. Products that are more than 6 months away from licensure at 
the time these proposed regulations may become effective would be 
expected to be fully compliant at the time of licensure.
    For products that are currently licensed, the standardized summary 
of efficacy and safety data and the revised labels would have to be 
submitted to APHIS within 4 years of the time these proposed 
regulations may become effective. Licensees could request an extension 
of up to 2 years for submitting these materials. Extension requests, 
which would have to include the reason for the extension and a proposed 
implementation schedule, would have to be submitted in writing to the 
CVB Director. Contact information for the Director can be found on the 
CVB Web site.
    Products whose original efficacy data are not available would 
require a statement on their data summary stating ``Original efficacy 
data is not available because the product was licensed ``x'' years 
ago.'' Regardless of the date of licensure of the product, any 
additional efficacy claims, including new routes of administration, or 
reference qualification data involving vaccination-challenge studies 
would be posted to the Web site. We believe that these timelines are 
appropriate for implementation of this proposed action and do not 
unnecessarily pose a hardship on the regulated industry or CVB.

Executive Orders 12866 and 13563 and Regulatory Flexibility Act

    This proposed rule has been determined to be significant for the 
purposes of Executive Order 12866 and, therefore, has been reviewed by 
the Office of Management and Budget.
    We have prepared an economic analysis for this rule. The economic 
analysis provides a cost-benefit analysis, as required by Executive 
Orders 12866 and 13563, which direct agencies to assess all costs and 
benefits of available regulatory alternatives and, if regulation is 
necessary, to select regulatory approaches that maximize net benefits 
(including potential economic, environmental, public health and safety 
effects, and equity). Executive Order 13563 emphasizes the importance 
of quantifying both costs and benefits, of reducing costs, of 
harmonizing rules, and of promoting flexibility. The economic analysis 
also provides an initial regulatory flexibility analysis that examines 
the potential economic effects of this rule on small entities, as 
required by the Regulatory Flexibility Act. The economic analysis is 
summarized below. Copies of the full analysis are available by 
contacting the person listed under FOR FURTHER INFORMATION CONTACT or 
on the Regulations.gov Web site (see ADDRESSES above for instructions 
for accessing Regulations.gov).
    Based on the information we have, there is no reason to conclude 
that adoption of this proposed rule would result in any significant 
economic effect on a substantial number of small entities. However, we 
do not currently have all of the data necessary for a comprehensive 
analysis of the effects of this proposed rule on small entities. 
Therefore, we are inviting comments on potential effects. In 
particular, we are interested in determining the number and kind of 
small entities that may incur benefits or costs from the implementation 
of this proposed rule. Further, we are interested in receiving 
information that could be used to further quantify the benefits of this 
proposed rule.
    APHIS is proposing to amend the Virus-Serum-Toxin Act regulations 
to require the use of a simpler labeling format. This simpler uniform 
format would allow biologics licensees and permittees to more clearly 
communicate product performance to the user. Biologics licensees and 
permittees would also be required to provide a standardized summary of 
the efficacy and safety data that are submitted to APHIS in support of 
the issuance of a full product license or conditional product license. 
The summary of efficacy and safety data would be made available to the 
public on the APHIS CVB Web site. We believe that the benefits of this 
rule justify the costs.
    A simpler, uniform format would allow biologics licensees and 
permittees to more clearly communicate product performance information 
to the end user. Veterinarians, the largest group of consumers of 
veterinary biologics, often find labeling indications statements based 
on the current guidance to be confusing, and have expressed a desire 
for indications statements to provide insight into the actual 
performance of the product, including summaries of safety and efficacy 
data. In addition, the rule would simplify the evaluation of efficacy 
studies, focusing on a basic claim of effectiveness compared to the 
more complex, tiered approach historically used by APHIS. The proposed 
rule would reduce the amount of time required by CVB to evaluate study 
data. Because complex claims require more complex studies, the rule 
would likely result in fewer studies being found unacceptable. A study 
that is determined to be unacceptable by APHIS can lead to significant 
costs to manufacturers. These costs include those associated with 
duplication of efforts and materials (facilities and animals) used when 
a study must be redone, and lost marketing opportunities when initial 
licensing applications are not approved. A novel veterinary biological 
product can generate revenue in the neighborhood of $5 to $10 million 
per year. Therefore, lost opportunities due to delays in bringing a 
product to market can be significant.
    This rule would affect all veterinary biologics licensees and 
permittees. There are approximately 98 veterinary biological 
establishments, including permittees. These companies produce about 
1,900 different products, and there are about 11,700 active approved 
labels for veterinary biologics. There were about 3,100 labels 
submitted for approval in the last 12 months by about two-thirds of the 
companies.
    Costs for licensees and permittees of the proposed rule are not 
expected to be significant, whether the affected entity is small or 
large. APHIS anticipates that the only costs associated with the 
proposed labeling format would be one-time costs incurred by licensees 
and permittees in having labels for existing licensed products 
reformatted in accordance with the proposed rule. Most biologics 
companies, in the course of normal business, use a just-in-time method 
for producing new labels and readily alter their content. Labels are 
regularly altered, for example, to enhance marketing through changes in 
design.
    Products that are not yet licensed but are within 6 months of 
licensure at the time these proposed regulations may become effective 
would be expected to be fully compliant no later than 1 year after 
licensure. Products that are more than 6 months away from licensure at 
the time these proposed regulations may become effective would be 
expected to be fully compliant at the time of licensure. For products 
that are currently licensed, the standardized summary of efficacy and 
safety data and the revised labels would have to be submitted to APHIS 
within 4 years of the time these proposed regulations may become 
effective. CVB would consider written requests to extend the time

[[Page 22051]]

period for submitting the summaries by an additional 2 years if 
necessary.
    In many instances manufacturers would not have to produce new 
labeling materials before they would do so in the normal course of 
business, and would only incur additional administrative costs to track 
the changes. Costs incurred for minor label changes that are 
coordinated with planned label changes are estimated to range between 
$99 and $500 per product with labels needing to be changed. We estimate 
that there are about 6,200 labels associated with about 1,000 products 
for which there would be this type of coordinated change. For these 
label changes, the total cost is estimated to range between $99,000 and 
$500,000.
    We expect that about 5,500 of the active labels, associated with 
900 products, would be changed other than in conjunction with a planned 
change. In these cases, manufacturers would incur costs for prepress, 
graphic design, and printing in addition to administrative costs. All 
labels for a specific product would be changed at the same time. Based 
on these activities, the costs of minor label changes that are not 
coordinated with planned label changes could range from $465 to $1,613 
in administrative and labor costs for each product with labels needing 
to be changed and from $100 to $275 per new label in materials cost. 
Because veterinary biologics manufacturers are likely to make changes 
for groups of products, all cattle products for example, there are 
likely to be savings in administrative and labor costs for those 
grouped changes. However, based on the above ranges, the total cost for 
these uncoordinated label changes is estimated to be between $968,000 
and $3 million.
    Minor costs may be incurred in producing the standardized summaries 
of efficacy and safety data for currently licensed products within the 
4-year implementation period. We estimate that about 1,700 summaries 
would need to be completed as a result of this rule because efficacy 
and safety studies are frequently provided for multiple products. The 
estimated cost would be about $55 per summary, or about $94,000 in 
total.

Executive Order 12372

    This program is listed in the category 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 7 CFR part 3015, subpart V.)

Executive Order 12988

    This 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 unless they present an irreconcilable conflict with this rule. 
The Virus-Serum-Toxin Act does not provide administrative procedures 
which must be exhausted prior to a judicial challenge to the provisions 
of this rule.

Paperwork Reduction Act

    This proposed rule contains no new information or recordkeeping 
requirements under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 
et seq.).

List of Subjects in 9 CFR Part 112

    Animal biologics, Exports, Imports, Labeling, Packaging and 
containers, Reporting and recordkeeping requirements.

    Accordingly, we propose to amend 9 CFR part 112 as follows:

PART 112--PACKAGING AND LABELING

0
1. The authority citation for part 112 continues to read as follows:

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

0
2. Section 112.2 is amended as follows:
0
a. In paragraph (a)(5), by adding a new first sentence.
0
b. By adding a new paragraph (a)(9)(v).
    The additions read as follows:

Sec.  112.2  Final container label, carton label, and enclosure.

    (a) * * *
    (5) An indications statement to read ``This product has been shown 
to be effective for the vaccination of healthy animals ------ weeks of 
age or older against ------.'' * * *
* * * * *
    (9) * * *
    (v) A statement similar to ``For more information regarding 
efficacy and safety data, go to http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/animalhealth?1dmy&urile=wcm%3apath%3a%2FAPHIS_Content_Library%2FSA_Our_Focus%2FSA_Animal_Health%2FSA_Vet_Biologics.''
* * * * *
0
3. Section 112.5 is amended as follows:
0
a. In the introductory text, by removing the words ``paragraph (c) of 
this section and under the master label system provided in paragraph 
(d)'' and adding the words ``paragraph (d) of this section and under 
the master label system provided in paragraph (e)'' in their place.
0
b. By redesignating paragraphs (b) through (g) as paragraphs (c) 
through (h).
0
c. By adding a new paragraph (b).
0
d. In newly redesignated paragraph (d)(1), by removing the citation 
``Sec.  112.5(d)'' and adding the citation ``Sec.  112.5(e)'' in its 
place.
0
e. In newly redesignated paragraph (e)(1)(ii), by removing the citation 
``Sec.  112.5(d)(1)(iii)'' and adding the citation ``Sec.  
112.5(e)(1)(iii)'' in its place.
0
f. In newly redesignated paragraph (e)(1)(iii), by removing the 
citation ``Sec.  112.5(d)(1)(i)'' and adding the citation ``Sec.  
112.5(e)(1)(i)'' in its place.
0
g. In newly redesignated paragraph (e)(1)(iv), by removing the citation 
``Sec.  112.5(d)(1)(ii)'' and adding the citation ``Sec.  
112.5(e)(1)(ii)'' in its place.
0
h. In newly redesignated paragraph (h), by removing the citation 
``Sec.  112.5(c)'' and adding the citation ``112.5(d)'' in its place.
    The addition reads as follows:

Sec.  112.5  Review and approval of labeling.

* * * * *
    (b) A data summary, available on the Internet at http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/animalhealth?1dmy&urile=wcm%3apath%3a%2FAPHIS_Content_Library%2FSA_Our_Focus%2FSA_Animal_Health%2FSA_Vet_Biologics, shall be used 
with each submission of efficacy and safety data in support of a label 
claim. Manufacturers will submit the efficacy and safety data 
information with either the efficacy and safety studies or at the time 
of label submission. This information will be posted at http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/animalhealth?1dmy&urile=wcm%3apath%3a%2FAPHIS_Content_Library%2FSA_Our_Focus%2FSA_Animal_Health%2FSA_Vet_Biologics to allow public 
disclosure of product performance.
* * * * *

    Done in Washington, DC, this 21st day of March 2014.
 Gary Woodward,
 Deputy Under Secretary for Marketing and Regulatory Programs.
[FR Doc. 2014-08995 Filed 4-18-14; 8:45 am]
BILLING CODE 3410-34-P
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